KCRS evaluated the safety, pharmacokinetics, pharmacodynamics, markers of tolerability, and acceptability of two types of 90-day continuous delivery tenofovir (TFV)-based IVRs for HIV prevention with and without pregnancy prevention at one clinical research site in Kisumu, Kenya. It enrolled healthy women aged 18–34 years who scored ≤4 on the validated Vaginal and Oral Interventions to Control the Epidemic (VOICE) HIV risk assessment tool [19]. KCRS clinical trial analyses and results are being published elsewhere.

Briefly, trial participants were randomized (2:2:1) to use one of the three IVRs: a TFV-alone IVR; a TFV/levonorgestrel (LNG) IVR, or a placebo IVR. Insertion and removal of IVRs was performed by a study clinician. The study clinic staff and participants were blinded to the randomization assignments; however, the trial was partially blinded because the TFV/LNG IVR appeared different from the TFV-only IVR. Although the TFV/LNG and placebo IVRs appeared the same, study clinicians may have been able to detect differences in the IVRs during insertion and removal. All participants visually inspected and briefly practiced self-insertion and removal of a placebo study IVR before randomization following standard biosafety and operation procedures. At all study visits, participants received non-spermicidal male condoms (as needed), HIV and pregnancy risk reduction counseling, and discussion of any potential side effects of using the IVRs. Participants were provided with 24-h telephone phone number to report all medical occurrences whether or not they were product related. Additionally, general health and genital examinations were completed at each study visit and participants were asked to document in a guidebook and to report all side-effects experienced. Clinical evaluation and management of side effects were handled separately from the qualitative interview. Participants randomized to use the TFV/LNG IVR might have also experienced changes in menstrual bleeding due to possible LNG-induced anovulatory cycles or breakthrough bleeding. Blinding was maintained until 1) the last enrolled participant had completed follow-up, 2) all endpoint data were entered into the study database, and 3) these data were verified as ready for final analysis. Planned IVR removal varied depending on each participant’s date of enrollment and ranged from one to three menstrual cycles.

Participants commonly expressed that they had little to no prior knowledge of IVRs before study recruitment activities took place in their communities. Participant recall of their initial reactions to IVR use focused on physical well-being fears that emphasized the likelihood of painful vaginal insertion and removal of the IVR; non-tolerability with prolonged use; physical discomfort (unnatural or foreign body sensation); the potential for the IVR to fall out or move within the body and possibly require surgical removal; disruption in women’s daily activities or inability to perform chores; non-acceptance by the participant’s significant others; the IVR being felt during sex, and concerns regarding infertility or other side effects that were comparable to or worse than those experienced with modern family planning methods.

Some participants expressed that overall safety of a MPT IVR was not a concern given that they had been assured by study staff that the government would not “allow something harmful to come to Kenya”. However, for a small minority of participants this translated to mean that the study IVRs had no side effects. With minor exceptions, participants described their IVR use experiences as positive (e.g., “very much okay”, “very satisfied”, “very happy”, “I loved it”). Feelings toward the IVR following actual use were depicted in terms of contentment (pleased with product) or discontentment (displeased with product). Product contentment was predominately attributed to having little to no side effects, physical discomfort, hindrance of daily activities, interference with sexual activities, or IVR expulsion. Some participants emphasized the benefit of not feeling the IVR and the ability to forget that it was in place.

Overall, participants indicated that study IVR side effects were temporary or manageable. While increased vaginal discharge was described by participants from each IVR group, mention by those randomized to the TFV/LNG IVR was more common. Participants indicated that increased vaginal wetness made daily use of pantyliners (provided by the study) necessary. They stated that the potential for increased vaginal wetness had been explained to them early on, so they felt prepared for it to occur. Despite considering the study IVR better than other contraceptive methods, one participant expressed product discontentment:

Concerns commonly noted by participants before IVR insertion included menstrual cycle suppression or increased bleeding. After initiating IVR use, abnormal vaginal bleeding (e.g., between cycle spotting, heavy menstrual flow) was occasionally described by participants. Heavy or prolonged menstrual cycles were rare. Lighter, and shorter menstrual cycles were reported by some participants. Participants did not express if lighter bleeding and shorter menstrual days were preferred. Those with a prior hormonal contraceptive history, commonly freely elicited assessments that the IVR made their periods “normal”.

Among the occasional participants who reported experiencing side effects associated with study IVRs, some indicated that the side effects diminished over time, while others encountered the same side effect or set of side effects throughout the study IVR use period. In some cases, side effects perceived to be related to IVR use may have been due to an undiagnosed medical condition (e.g., anemia as suggested by the quote below).

Along with the participant quoted above, a few participants described sensations of the IVR repositioning, slipping down, or slipping out of place.

Participants otherwise indicated that the IVR remained in place despite their initial concerns that menses, physical activities, sex, or body elimination processes would expel it. Being able to feel the IVR created some physical discomfort to a few participants.

Despite frequent statements by participants by that side effects would greatly influence IVR acceptance, descriptions regarding side effect reporting and management experiences were limited. While the majority of participants who experienced side effects stated that they “did as instructed” and sought out assistance from the study clinicians in managing their side effects, there was one participant who acknowledged inconsistent reporting.

Participant comments related to the IVR’s physical properties were rare. A few participants mentioned that they recalled having size concerns (i.e., “too big”) prior to using the study IVR. After experiencing IVR use, only one participant commented that the community may not accept an MPT IVR unless the size is made smaller.

While participants acknowledged the unproven efficacy of study IVRs and spoke of being randomized to one of three rings, a few participants were unclear on the prevention aim of all the IVRs beyond there being one to prevent HIV. While unique, the design (“wide open”) of the IVR raised pre-use questions for a few participants as to how the IVR worked or could be effective. Other participants either questioned how the drug would get released into their bodies from the IVR or if the IVR would be “a protective” delivery mode [i.e., would actually work in providing protection from pregnancy or HIV].

In discussing acceptance, participants commonly framed their responses around a MPT IVR “helping women”, “saving lives” and “being useful” and recommended that the IVR’s benefits be prominently highlighted. Participants indicated that questions or uncertainties regarding efficacy would nonetheless be present; however, such concerns could best be addressed by allowing users to share their experiences with the community at large or inviting women the opportunity to try it out for themselves.

Some participants stressed the importance of not restricting use of a MPT IVR to particular groups. These participants highlighted the appropriateness of making an efficacious MPT IVR accessible to adolescent and young women. Conversely, other participants firmly maintained that a MPT IVR should not be used by women without a history of at least one childbirth or by those who are not yet married.

Participants explained that the availability of an IVR for preventing HIV infection would help alleviate societal and personal HIV burdens, especially given that there is no available cure for HIV. Concerns for the welfare of children who had one or both parents die from HIV were common. The idea of a MPT IVR providing an effective method for avoiding unplanned pregnancy, especially among adolescent girls and young women, was generally viewed favorably (e.g., supports child spacing, improves health and socioeconomic outcomes for women and their children). This was also considered potentially controversial given personal and hearsay accounts of side effects due to family planning methods and viewpoints that family planning methods could cause infertility or negative birth outcomes. Participants also indicated that a MPT IVR would help get around needing to use a condom or convincing a sexual partner that condoms were necessary. The need to combine condom use with a MPT IVR to prevent STIs was rarely mentioned.

Participants often spoke of an accidental HIV exposure (e.g., needle stick, coming into contact with an injured person’s blood, unknown HIV status of a sexual partner) or pregnancy resulting from non-consensual sex. Hence, a MPT IVR was viewed as being highly beneficial in the context of physically forced or unwanted [tricked, manipulated, or coerced] sex, having an HIV-positive partner, or having a sexual partner who engaged in sexual behaviors that placed a woman at increased risk for HIV infection. Although not a property of MPT IVRs, a few women believed that a MPT IVR would also afford men protection.

A commonly perceived benefit of a MPT IVR centered on avoiding daily medication necessary to either treat or prevent HIV. Along with a MPT IVR being longer acting than oral contraceptives, it was viewed as less burdensome (no need to remember to take daily) given that the user could potentially insert and remove the IVR, especially if pregnancy was desired or side effects were problematic. A minority of participants mentioned that a drawback of the user removing the MPT IVR for any reason was the immediate absence of protection. One participant shared that curiosity led her to remove the study IVR temporarily to observe changes in the device. Of note, while all study IVRs remained the same size when inside and outside of the vagina, this participant held that environmental-related expansion and contraction differences were observed.

Participants indicated that having to expend less time and effort (e. g., travel time, time away from work, frequency of clinic visits) to access a MPT IVR through existing medical channels could further product appeal and acceptance. Participants stated that the fewer challenges a woman faced in using a MPT IVR, the better user compliance and adherence could potentially be for them. A MPT IVR was also described by some participants as having the added benefits of either minimizing or helping to overcome stigma (i.e., “won’t look down upon you”). They explained that unlike daily oral PrEP or contraceptives, such as oral pills or an implant, others in the community would not likely be aware that a woman was using a MPT IVR.

Although all participants reiterated the dual HIV and pregnancy prevention in discussing a potential MPT IVR, they rarely explicitly stated (as illustrated by the quote below) that having two products in one offered convenience to the user, as opposed to having to use various products for each indication.

After initiating IVR use, participants commonly held that an IVR that simultaneously protected against HIV and pregnancy would be favorably received by others in the community. However, participants also acknowledged a stronger likelihood that receptivity within the community would be mixed and that it was mainly attributed to the contraceptive co-formulation of a MPT IVR. Participants shared that despite community recognition of the negative socioeconomic, health, interpersonal, and structural consequences of unplanned pregnancy, some sexual partners, family members, influential leaders, and decision-makers would be reticent to accept a MPT IVR. Participants noted that the hesitancy could be due to existing unfavorable attitudes toward modern family planning methods, including condoms. Often, family planning methods were described as being inconvenient, requiring compliance (on-time, every time) which was often difficult, and leading to potential side effects, such as heavy prolonged bleeding, the inability to conceive, and cervical cancer.

User testimonial and endorsement by local health professionals were perceived to be essential in attaining community support. Opposition by family, friends, village elders, religious leaders, and others could discourage IVR knowledge and use. Men were described as less willing to accept a MPT IVR. In addition to the health and female sexuality concerns, any potential for diminished sexual interest or desires on a woman’s part or the IVR being felt during sex was perceived to limit acceptance by men. Participants stressed the importance of educating the community about MPT IVR risks and benefits given the significant role that rumors, and misinformation could have on acceptance and permission by partners and family members to use it. Having a MPT IVR that was tried and tested within the community was perceived to further foster support for the IVR.

From a sociocultural perspective, a few participants shared that the IVR should only be used by women who had already given birth to one or more children, given the potential for the IVR to prevent them from having children in the future. Community members opposed to a MPT IVR were described as likely to focus on family planning concerns, to believe that an IVR would increase premarital and extramarital sexual activity, sexual promiscuity, and participation in transactional sex by women.

Pros and cons of being able to discreetly use an IVR without a partner’s knowledge were discussed by most participants. Non-acceptance by partners was often attributed to concerns regarding a woman’s fidelity.

Some participants informed their sexual partners about the IVR in advance given that study staff had indicated that male partners might be able to feel the IVR during sexual intercourse. Others opted not to disclose study IVR use to anyone, including their partners. Descriptions of partners being able to feel a study IVR were uncommon.