Acceptability of a Dapivirine/Placebo Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-026)

Abstract

This study describes the acceptability of a rectal microbicide gel formulation using dapivirine (DPV) among men and women from two countries (United States and Thailand) participating in the Microbicide Trials Network-026 trial. We evaluated participants’ acceptability of a rectal DPV/placebo gel as part of a Phase I trial (N = 26; 18 male, 8 female). Participants reported favorable acceptability of the study gel, with most participants reporting that they liked the gel the same (n = 14; 53.8%) or more (n = 11; 42.4%) than when they started the trial. Over half of participants noted that they would prefer the gel over condoms (n = 13; 50%) or that they liked condoms and the gel equally (n = 8; 30.8%). Side effects across products included leakage (n = 8; 30.8%), diarrhea (n = 4; 15.4%), or soiling (n = 1; 3.8%). The high acceptability of a rectal gel underscores its promise as a short-acting biomedical prevention, warranting future research for HIV prevention.

Trial Registration: NCT03239483.

Introduction

Background

An estimated 1.7 million individuals acquired HIV in 2019 [1]. The Centers for Disease Control and Prevention (CDC) estimates that the per-act probability of acquiring HIV through sexual behavior is greatest for individuals who engage in receptive anal intercourse (RAI; 138 per 10,000), followed by insertive anal intercourse (11 per 10,000), and receptive penile-vaginal intercourse (8 per 10,000) [2]. The success of daily oral pre-exposure prophylaxis (PrEP) as a biomedical HIV prevention method has energized researchers’ and advocates’ call for additional short-acting (e.g., PrEP lubricants, PrEP douches) and long-acting (e.g., PrEP injectables, PrEP implants) biomedical prevention options [3–7]. These alternative methods of biomedical prevention may help overcome some of the uptake and adherence challenges linked to daily oral PrEP [8–10].

Rectal microbicides (RM) are topical biomedical products being developed to reduce the risk of HIV or other sexually transmitted infections [7, 11, 12]. Previous studies have looked at the pharmacodynamics and pharmacokinetics of various microbicide gels for HIV prevention [13–15]. Findings from these studies suggest that gels might protect against HIV, yet current data suggest lower efficacy levels than daily oral PrEP, due to challenges in modality of administration, drug formulation, and adherence [13–15].

Morrow and Ruiz developed a comprehensive and integrated framework to assess microbicide acceptability across diverse phases of clinical trials [16]. During Phase I trials, for example, Morrow and Ruiz suggest that researchers assess how factors related to the microbicide vehicle (e.g., formulation, texture and viscosity), application (e.g., need for an applicator, ease of use, portability), and use (e.g., behavioral congruence; side effects) influence the acceptability of an innovative prevention drug. Utilizing Morrow and Ruiz’s approach, researchers have found a variety of facilitators and barriers regarding gel acceptability and adherence [17–21]. Participants who have tested rectal gels have found routine incorporation [22–24], discretion [25, 26], and ease of gel use when engaging in unprotected rectal intercourse [25–27] to be important facilitators to a gel’s acceptability and adherence. However, barriers have also been identified, including challenges regarding the application process [22, 28], physical discomfort [22, 23], and formulation volume [21] and viscosity [26]. These barriers and facilitators have been linked to individuals’ willingness to use an effective microbicide in the future, further reinforcing the value of examining factors linked to product acceptability during early stages of clinical testing.

This study describes the acceptability of a RM gel formulation using dapivirine (DPV) and placebo gels among men and women from two countries (United States and Thailand) participating in the Microbicide Trials Network (MTN)-026 trial [29]. Dapivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a substituted di-amino-pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1. Previous work has identified support for the favorable safety profile and tolerability of DPV as a microbicide ring vaginal use [30–32]. For MTN-026, an HTI Plastic pre-filled applicator was utilized with each applicator being prefilled with approximately 2.5 g (2.5 mL) of gel (DPV or placebo). Accounting for the previous work and promise of an effective rectal microbicide gel, the MTN-026 study was designed as a Phase 1, randomized, double-blind, multi-site, placebo-controlled trial designed to evaluate the safety and acceptability of DPV gel (0.05%) when administered rectally to healthy men and women who tested negative for HIV-1 and HIV-2.

Methods

Sample

Twenty-six evaluable men and women were randomized to two arms: (1) a gel containing DPV (0.05%) or (2) a universal hydroxyethylcellulose (HEC) placebo gel. Data collection took place between December 2017 and September 2018 in two cities in the United States (Pittsburgh, Pennsylvania and Birmingham, Alabama), and in Bangkok, Thailand [29]. Participants were recruited through clinic registries of former participants interested in future studies, community outreach events, and word of mouth.

Inclusion criteria included (1) between the ages of 18 and 45 years old; (2) testing negative for HIV-1 and HIV-2; (3) able and willing to provide adequate locator information; (4) able to return to all study visits and willing to comply with participation requirements; (5) in general good health at screening and enrollment visits; (6) have a history of consensual RAI at least once in the past calendar year; (7) willing to not take part in other research studies involving drugs, medical devices, genital or rectal products, or vaccines for the duration of study participation, including the time between Screening and Enrollment; (8) willing to be sexually abstinent for 72 h prior to each study visit, during the study product use periods, and for 72 h after biopsy collection; (9) willing to abstain from inserting any non-study products into the rectum for 72 h prior to each study visit and during the study product use periods. Additionally, cis-gender female participants had to: (1) document a satisfactory cervical cytology smear within the past 3 years prior to Enrollment; (2) be sexually abstinent for 72 h prior to each study visit and during the study product use period and for 7 days after biopsy collection; (3) abstain from inserting any non-study products into the vagina for 72 h prior to each study visit, during the study product use periods, and for 7 days after biopsy collection; and (4) use an effective method of contraception for at least 30 days (inclusive) prior to Enrollment and agree to continue use of an effective method for the duration of the study participation.

The study was reviewed and approved by the Institutional Review Boards (IRBs) at all participating institutions. All enrolled participants provided written informed consent to voluntarily participate in the trial. Participant reimbursement was based on local guidelines and approved by the local IRB prior to study implementation.

Clinical Procedures

Participants were screened for eligibility prior to enrolling in the study (see Fig. 1 for a summary schedule of the study visits). Participants returned to the clinic within the 45-day screening window (Visits 1 and 2) where they completed administrative, behavioral, and clinical and laboratory procedures. Additionally, clinical results or treatments for urinary tract infections, reproductive tract infections, sexually transmitted infections (UTIs/RTIs/STIs) or other findings were completed as clinically indicated at all visits.

Fig. 1.

Study visit schedule

During Visit 3, participants had the study product administered by study staff. At this and subsequent visits (Visits 4 to 6), participants completed administrative, behavioral, clinic and laboratory procedures, including intensive collection of biological samples for PK and safety analyses.

After a minimum 14-day washout period, participants returned to the clinic to initiate the directly observed dosing (DOD) with product administered either by the participant or by study staff, depending upon site and/or participant preference (Visits 7–13). Participants were provided illustrated instructions on how to insert the rectal gel with the applicator, including details on how to remove the applicator and plunger from the wrapper, insert the plunger into the prefilled applicator barrel, and then remove the blue cap from the end of the barrel. Each participant was given one applicator to take home at the start of the 7-day dosing period to be used in case they could not attend their clinic visit. During Visit 13, participants completed administrative, behavioral, clinic & laboratory procedures, as well as the final administration of the study product. In Visits 14, 15, and 16, participants returned to the clinic site to complete administrative, behavioral, clinic and laboratory procedures, including providing pharmacokinetic (PK) and pharmacodynamic (PD) samples. Participants were asked to be sexually abstintent for 72 h prior to each study visit, during the study product use periods, and for 7 days after biopsy collection.

Visit 17 served as the follow-up safety contact and termination visit during which participants complete administrative and regulatory procedures as well as receive clinical results or receive treatment for UTIs/RTIs/STIs or other findings, if indicated.

Behavioral Procedures

Participants completed a baseline computer assisted self-interview (CASI) during their enrollment visit, a brief CASI on product acceptability and adherence during Visit 3, and an exit behavioral survey at their Visit 14. For the purposes of this report, we include data from participants’ baseline questionnaire (e.g., sociodemographic characteristics) and their exit questionnaire (e.g., product acceptability indicators). Additionally, participants completed two in-depth video interviews (IDIs) with research staff (Visits 3 and 14).

Survey Instruments

Sociodemographic Characteristics

Participants completed a baseline CASI where they self-reported sociodemographic characteristics, including age, sex assigned at birth and current gender, race/ethnicity using the United States Office of Management and Budget categories for participants in the US sites. Participants in the Thailand site were classified as Thai nationals. Participants could identify their sexual identity as heterosexual, gay, bisexual, or another other category with the instruction to specify what their identity was. Participants were also asked to note if they had a primary partner, their employment status, and their highest level of educational attainment (see Table 1). Participants were also asked to report the number of male sexual partners with whom they had sex in the 30 days prior to their baseline survey.

Table 1.

Self-reported demographic characteristics of evaluable participants (N = 26)

Sociodemographic characteristics	M (SD)/N (%)	US participants (n = 14)	Thai participants (n = 12)	t/X2 statistic
Age (years)	30.8 (7.73)	33.75 (6.88)	27.75 (7.91)	1.98
Sex assigned at birth				0.04
Male	19 (73.1%)	10 (71.4%)	9 (75.0%)
Female	7 (26.9%)	4 (28.6%)	3 (25.0%)
Current gender				0.07
Male	18 (69.2%)	10 (71.4%)	8 (66.7%)
Female	8 (30.8%)	4 (28.6%)	4 (33.3%)
Race/nationality
Asian	1 (3.8%)	1 (7.14%)
Black or African American	5 (19.2%)	5 (35.72%)
White	8 (30.8%)	8 (57.14)
Thai	12 (46.2%)		12 (100%)
Sexual identity				1.24
Gay/homosexual	13 (50.0%)	6 (46.2%)	7 (58.3%)
Straight/heterosexual	5 (19.2%)	3 (23.1%)	2 (16.7%)
Bisexual	6 (23.1%)	3 (23.1%)	3 (25.0%)
Other	1 (3.8%)	1 (7.7%)	0 (0.0%)
Missing	1 (3.8%)	1 (7.7%)	0 (0.0%)
Has a primary partner	12 (46.2%)	8 (57.1%)	6 (50.0%)	0.13
Employment status				1.40
Full-time	9 (34.6%)	6 (42.9%)	3 (25.0%)
Part-time	10 (38.5%)	4 (28.6%)	6 (50.0%)
Unemployed	7 (26.9%)	4 (28.6%)	3 (25.0%)
Education				1.39
Partial high school/secondary school	1 (3.4%)	1 (7.1%)	0 (0.0%)
Partial college	12 (46.2%)	7 (26.9%)	5 (41.7%)
College graduate	5 (19.2%)	2 (7.7%)	3 (11.5%)
Partial graduate school	2 (7.7%)	1 (7.1%)	3 (11.5%)
Graduate school degree	6 (23.1%)	3 (21.4%)	3 (11.5%)
Number male sex partners (past 30 days)	1.35 (1.0)	1.50 (2.57)	1.17 (1.12)	0.42

Product Acceptability

As part of their exit survey, participants were asked to complete several items consistent with Morrow and Ruiz’s framework (see Table 2). Participants were asked about vehicle-related characteristics (e.g., feeling of gel inside their body), application-related characteristics (e.g., process of application; ease of application; application problems experienced), and use-related characteristics (e.g., ease of using the gel, problems using product, perceived side-effects post-use). Participants also shared their views on the overall acceptability of the gel and whether their views on acceptability of the gel had changed since the beginning of the study.

Table 2.

Participants’ product acceptability evaluation at the exit survey (N = 26)

Domain	M (SD)/N (%)
	Total sample, N = 26	Male, n = 19	Female, n = 7	X2 statistic	US participants (n = 14)	Thai participants (n = 12)	X2 statistic
Application-related characteristics
Liked/Liked Very Much the gel application process	13 (50.0%)	10 (52.6%)	3 (42.9%)	.20	8 (57.1%)	5 (41.7%)	.62
Gel was “Easy”/”Very Easy” to insert?	19 (73.1%)	17 (89.5%)	7 (100%)	.80	13 (92.9%)	11 (91.7%)	.01
Did you have any problems using the applicator to insert the gel rectally?	2 (7.6%)	2 (10.5%)	0 (0%)	.80	2 (14.3%)	0 (0.0%)	1.86
Use-related characteristics
Gel use was “Easy”/“Very Easy”a	25 (96.2%)	18 (94.7%)	7 (100%)	.39	14 (100%)	11 (91.7%)	1.21
Gel use was “Comfortable”/“Very comfortable” b	22 (84.6%)	16 (84.25)	6 (85.7%)	.01	11 (78.6%)	11 (91.7%)	.85
Perceived side-effects after product use
Leakage	8 (30.8%)	5 (26.3%)	3 (42.9%)	.66	6 (42.9%)	2 (16.7%)	2.08
Soiling of underwear or linens	1 (3.8%)	0 (0%)	1 (14.3%)	2.82	1 (3.8%)	0 (0.0%)	.89
Diarrhea	4 (15.4%)	3 (15.8%)	1(14.3%)	.39	3 (21.4%)	1 (8.3%)	1.19
Overall acceptability post-study use
Liked or Liked Very Much the gel “?c	24 (92.3%)	17 (89.5%)	7 (100%)	.80	12 (85.7%)	12 (100%)	1.86
How do you like the gel now compared to when you started the study?				.39			2.82
I like it MORE now than when I started the study	11 (42.4%)	8 (42.1%)	3 (42.9%)		4(28.6%)	7(58.3%)
I like it the SAME as when I first started	14 (53.8%)	10 (52.6%)	4 (57.1%)		9(64.3%)	5(41.7%)
Not applicable, I do not like the gel	1 (3.8%)	1 (5.3%)	0 (0%)		1(7.1%)	0(0.0%)
Future use
If in the future a rectal gel was available that provided some protection against HIV, and it was similar to the one you used in this study, which would you prefer to use: the study gel, the male condom, or both?				2.40			1.43
Gel	13 (50%)	9 (47.4%)	4 (57.1%)		6 (42.9%)
Condom	4 (15.4%)	2 (10.5%)	2 (28.6%)		2 (14.3%)	7 (58.3%)
Neither—I dislike both products	1 (3.8%)	1 (5.3%)	0 (0%)		1 (7.1%)	2 (16.7%)
Both – I like both products equally	8 (30.8%)	7 (38.6%)	1 (14.3%)		5 (35.7%)	0 (0.0%)
What do you think your primary partner would prefer?				3.13			1.86
Gel	6 (23.1%)	4 (21.1%)	2 (28.6%)		3 (21.4%)	3 (25.0%)
Condom	6(23.1%)	4 (21.1%	2 (28.6%)		4 (28.6%)	2 (16.7%)
Both—likes both products equally	2 (7.7%)	1 (5.3%)	1 (14.3%)		1 (7.1%)	1 (8.3%)
Don’t know	6 (23.1%)	4 (21.1%)	2 (28.6%)		4 (28.6%)	2 (16.7%)
I don’t have a primary partner	6 (23.1%)	6 (31.6%)	0 (0%)		2 (7.7%)	4 (33.3%)

^aNumber of participants who selected “Easy” or “Very easy” as response to question: “Overall how easy was it to use the gel?”. Note that the response options were not consistent between sites: participants in the US sites were given four options (“Very difficult”, “Difficult”, “Easy”, “Very easy”) while participants in the Bangkok site were given an additional option (“Neutral”)

^bNumber of participants who selected “Comfortable” or “Very comfortable” as response to the question: “Overall how did it feel to have the gel inside you?”. Note that the response options were not consistent between sites: participants in the US sites were given four options (“Very comfortable”, “Comfortable”, “Uncomfortable”, “Very uncomfortable”) while participants in the Bangkok site were given an additional option (“Neutral”)

^cNumber of participants who selected “Liked” or “Liked Very Much” as response to the question: “Overall, how much do you like the gel?”. Note that the response options were not consistent between sites: participants in the US sites were given four options (“Liked very much”, “Liked”, “Disliked”, “Disliked very much”) while participants in the Bangkok site were given an additional option (“Neutral”)

The Thailand site IRB requested that an additional answer category (“Neutral”) be added to the acceptability questionnaire. Unfortunately, the US sites had already started enrollment and data collection when this request was made by the Thailand site prior to their site’s activation. As a result, Participants in the US sites were given four response options (“Very difficult”, “Difficult”, “Easy”, and “Very easy”; “Very Comfortable”, “Comfortable”, “Uncomfortable” and “Very Uncomfortable”) for these questions, whereas participants in the Bangkok site were given an additional option (“Neutral”) to accommodate the site’s feedback on the answer categories, for a total of five response options. To address this difference in response categories, we dichotomized our acceptability indicators (see Table 2) so that the “Neutral” category would not affect our interpretation (e.g., 1 = Easy/Very Easy; 0 = all other answers; 1 = Comfortable/Very Comfortable vs. 0 = all other answers).

Future Use

Participants were asked to indicate their likelihood of using a rectal gel microbicide in the future relative to condoms. Participants could answer using one of the following responses: “Gel”, “Condom”, “Neither—I dislike both products”, “Both—I like both products equally”. Similarly, participants were asked to indicate what they perceived was their male sexual partner’s preference for a HIV prevention method using one of the following responses: “Gel”, “Condom”, “Neither—dislikes both products”, “Both—likes both products equally”, “Don’t know”, or “I don’t have a primary partner”.

Qualitative Exit In-Depth Interview

After completing their follow-up (Visit 3) and exit (Visit 14) behavioral CASIs, participants completed an online IDI with trained qualitative interviewers located at a partner research institution in the US. The interviewer for the Thai site is a native Thai speaker.Only the audio portion of the IDI was recorded. Both interviewers had prior experience conducting qualitative interviews, were trained in the study-specific procedures, and completed mock interviews prior to the start of the data collection. Both interviewers maintained the same participants from their first interview (Visit 3) to their second (Visit 14).

In preparation for the IDIs, the interviewers examined participants’ CASI data across Visits 3 and 14 to identify domains that might require clarification during the IDI. A total of 53 interviews were completed (one participant did not attend the last study visit) using a semi-structured interview guide that explored participants’ general study experiences, gel perceptions, experiences with direct observation, gel acceptability, and anal sex experiences. Acceptability probes explored general impressions of the gel, perceived ease or difficulty of insertion and use, physical and emotional discomfort attributed to the gel, daily use of the gel, perceived ability to discuss the gel with a sexual partner, likelihood of using the gel to prevent HIV, and factors that would either prevent or encourage gel adherence. Clinic staff excused themsevles from the room to afford the participant privacy during their interview. The audio was transcribed verbatim, translated into English (Thai transcripts only) by the Thai interviewer, de-identified, and checked for accuracy. Interviews lasted an average of 45 min (range = 15 to 69 min). Interviewers kept notes during the interview and were saved to the participant files. Transcripts were not returned to participants for comment and/or correction.

Data Analytic Strategy

We used IBM SPSS, version 27, to compute descriptive statistics (e.g., percentages, means and standard deviations) from CASI data. We performed tests of hypothesis to evaluate if participants’ experiences with the study products differed across study arms. As a sensitivity analysis, we also examined whether participants’ acceptability scores differed by trial site and sex assigned at birth. No differences between arms, sex assigned at birth, or site were observed for any of the evaluated characteristics in our bivariate analyses.

The research team developed a codebook guided by the major areas of interest and probes from the interview guide and the four major acceptability domains based on Morrow and Ruiz’s framework: (1) gel application and usability; (2) gel characteristics and sensation; (3) gel knowledge and side-effects; and (4) considerations for future use. The codebook included code names, explicit definitions, and inclusion and exclusion criteria to ensure coding accuracy. To validate and finalize the codebook, three researchers independently coded three transcripts and discussed coding discrepancies to reach consensus. The codebook was then updated as needed for clarification. All transcripts were coded independently by two members of the team, who then met to discuss the codes assigned to each transcript. Any discrepancies between coders were resolved with input from a third coder to reach consensus. Thematic analysis [33] was facilitated by Dedoose, version 7, an online web application for qualitative data analysis.

For the mixed methods analysis, we employed a convergent parallel design [34]. Consistent with this strategy, the quantitative and qualitative data were analyzed separately and then brought together to examine where there was convergence or disagreement between the data sources. The team also examined whether the themes and exemplars offered by participants regarding the study product differed [35] based on participants’ study site. We compared and contrasted how participants discussed the themes within and between groups, and found no apparent differences in how participants’ discussed or perceived the study product. Illustrative participant quotes, alongside age, product assignment, country and gender, are included in Table 3 as well as embedded in the Results section below.

Table 3.

Exemplar quotes from study participants across acceptability domains and factors

Domains	Factors	Quotes
Application associated factors	Clarity of instructions (application & usability)	I: How clear were the instructions with applying and inserting the gel? P: Very clear. There were diagrams I: Ok. And the diagrams were simple to understand and everything? P: Right. So, if someone can’t read very well, they’ll still pretty much get it I: When they said something, do you remember when they said P: They gave me instructions on how to use the gel I: Did you ask them any questions? P: Not really
	Ease of application (application & usability)	I: So, can you tell me about your experiences with inserting the gel over the seven day period? P: Yea, sure. It was easy. I will say the only thing I had a issue with was that like I wasn’t sure sometimes if it was in, if the gel was applied at the a region or like depth that I needed it to, or that I got all the gel out. Like you insert the applicator and released it in there but like it would be more helpful if the applicator was clear so maybe you could see like the contents and how much you needed, like how much was in there. I couldn’t really; I didn’t know how much gel was in the applicator so even when I put it into the rectum…I wasn’t sure like, was that a lot? Was that a little? Was it all gone? Is it not there? I: The next part will be your experience with gel insertion and direct observation therapy. How did you feel about the clinic staff member inserting the gel into your body? P: Other people might not know the angle of inserting the gel. There was one staff member who did it for me and she knew how to do it. The process was then painless. There were then some staff members who did not know the angle, so it was hurting a bit. However, it was not like an unbearable pain or anything like that. I was able withstand it. I think of all the time that I had the gel inserted, I felt hurt only once. As for having others putting it in, I didn’t feel embarrassed about it. Overall, I felt nothing when they inserted the gel
Use-associated factors	Desirable/appealing elements of use (future use)	I: Can you tell me about why would you be extremely likely to use the gel in the future? P: I can just be like honest and crass and whatnot? I: Yeah P: Because that to me seems like the best alternative to just not using a condom. So like I personally don’t like using condoms, so when you tell me that there is a gel that kind of does the actual work, or can do the actual work, of my just guesswork (laughs). Then that to me is even more reassuring and it gives me a greater sense of confidence. Now if I were someone who already used, who did use condoms as frequently as maybe I should, then that would be like a straight up, like 100% yes I’ll do it, because like it’s, it’d be extremely safe, like in addition to me already using condoms, right? But as someone who doesn’t really prefer to use them, it’s like imagine being someone who doesn’t use condoms and hearing this information… “Oh, well there is something that still helps in prevention, etc. that isn’t a condom and that bypasses that, then like, oh my god, absolutely.” I: At the beginning of the study, you mentioned that if there were a similar rectal gel available that provided some protection against HIV, would it be likely for you to use the gel? P: I think it’s an alternative. I can use this gel along with a condom. I would feel more confident when I have sex I: You mentioned that it would be likely that you would use the gel. Now you’ve used the gel for 7 days. Has that opinion changed? P: It’s still the same. Nothing changed I: You mentioned that if it could protect against HIV to some extent, it would be likely for you to use this product. What would it be likely for you to use the gel? P: It’s added assurance. Let’s say I can use it with a boyfriend. I trust this person, so I can use this gel for protection without using a condom. But, it would be only with a boyfriend only that I will be confident to only use this gel. It’s a level of protection
	Leakage (side-effects)	I: And after the, after the gel was inside, how was the feeling? You mention there wasn’t anything but do um once it was inside and kind of you were walking over to the other place, how did it, did you feel anything? P: Yeah, I initially had a feeling. I was going to ask my nurse: “I feel that it’s leaking..”, but I think because of the consistency, I thought it has to leak. It was not so thick and so I didn’t mention to nurse about the leakage but that’s it I mean, I didn’t feel uncomfortable with the gel I: Now we will talk about your experience using the study gel. Did you have trouble using the gel? P: I didn’t have any diarrhea or any stomachache. I didn’t feel uncomfortable. I only feel pain a bit when they inserted the gel. That’s pretty much it. It doesn’t leak or making the area around (the insertion area) dirty
Vehicle associated factors	Texture/viscosity (gel characteristics)	I: Do you think this study gel has any advantages that perhaps you didn’t think about it before? You mentioned that it didn’t leak. Does the study gel have any other advantage? P: I think that they might adjust the viscosity or something along that line. In the beginning after the insertion, I imagined the gel to be clear and it might leak. After they pulled out the suppository, it didn’t leak. I think that they have improved on it I: How do you mean? Comparing to what? P: I’m talking about other gels in the market, other products. Gels that I use normally are sticky. They’re icky. I don’t feel that the area is dirty that I have wash it off. I feel clean afterwards I: Being one the few people who have actually used the product, could you talk about the consistency a little bit? P: The one thing I did like about it is once I finally got it in there, there was no… Once I got it in there, you didn’t feel anything sloshing around or anything like that. It was in there and I forgot about it. Other than the fact that I knew I put it in there, I forgot about. There is nothin’ goin’ on in there to let you know that there’s some gel in there, and that’s one thing I really really liked about it is you could put it in there and you could go on, you could forget about it. There was definitely no seepage, no leakage, which I really liked. So, it was a really good consistency to me

Results

The mean age of participants was 30.8 years (SD = 7.73), with 18 participants (69.2%) identifying as cis-gender men, 7 (26.9%) participants identifying as cis-gender women, and one (3.8%) participant identifying as a transgender woman. With regards to race/ethnicity, participants in the US clinical sites self-identified as White (n = 8; 30.8%), Black or African American (n = 5; 19.2%), or Asian (n = 1; 3.8%). All participants in the Thailand site identified as Thai (n = 12; 46.2%). Over 80% of the sample reported as gay or bisexual. Five participants (n = 5; 19.2%) identified as heterosexual, one participant self-identified as pansexual in the write-in option for “Other” sexual identity option (n = 1; 3.8%), and one participant did not answer the question (n = 1; 3.8%) (see Table 1).

Overall, participants reported favorable acceptability to the study gel post-use, with 22 (84.6%) participants reporting that the gel was comfortable or very comfortable. Most participants (n = 24; 92.3%) reported liking the gel. Most participants reported that they liked the gel the same (n = 14; 53.8%) or more (n = 11; 42.4%) than when they started the trial (see Table 2).

Prior Gel Use

Participants discussed a variety of preferences for the lubricants that they use. Of the participants who provided feedback on their lubricant usage, most participants (n = 18; 90%) mentioned using lubricant regularly or every time they have anal sex. Several participants mentioned primarily using water-based lubricants, while others mentioned using silicone-based lubricants. Additionally, some of the phrases used by participants to describe the amount of lubricant they used varied from “a lot of lube” to and “just whatever feels covered.”

Additionally, participants were interested in obtaining information regarding drug efficacy and effectiveness when the study is finalized, and results are disseminated. Some participants indicated they would like to know how many uses or how frequently use is required for efficacy, and that they would generally like to know if the product is effective at its intended purpose.

“I think after you research on the drug allergy, you have to research in terms of the delivery of the drug. I’m just concerned about when the medicine is inserted inside the rectum and let’s say it’s coated on one side of the wall, but not the other. Would that be a risk? That’s the part that I’m curious about.” (Thai Participant #19, age 39, Dapivirine Gel Arm, Male)

Participants also discussed what the product meant for the potential for HIV prevention. While most participants felt that HIV prevention was the most important characteristic of the gel, they also suggested marketing product as a gel that serves the dual purpose of providing lubrication and HIV prevention.

“I would, probably the same way I did before. I mean it’s a gel. It definitely could be used as a lubrication but also it’s like a double hitter. It’s a lubricant and it’s medication to help prevent to save your life from HIV.” (Pittsburgh Participant #7, age 34, Placebo Gel Arm, Female)

Gel Application & Usability

When asked about the application process, participants were evenly split (50%) when asked if they liked the gel’s application process. We found no differences by study arm ($X_{(1)}^2=0.17$, n.s.), sex assigned at birth or study site (see Table 2). When asked about the ease with which they could insert the gel, most participants (73.1%) reported that inserting the gel was easy, with no differences by study arm (($X_{(1)}^2=0.23$, n.s.), sex assigned at birth or study site (see Table 2). In interviews, participants shared that applying the gel on their own contributed to participants feeling a greater sense of comfort. As one participant noted,

“I inserted it myself over those seven days um the staff was in the room. And there was nothin’ to it. I know I told you previously that I felt like the gel applicator needed to be redesigned. That’s because the first time it was inserted, I never saw the applicator. […] I think maybe she had went in at maybe a not so great angle, which kind of caused a little bit of discomfort. But once I finally saw the applicator, I was like “oh, this is great, this is, this is awesome.” So, once I finally got a chance to, ‘cause I know my body more than she does. […] So once I finally got a chance to actually do it myself, the design is great. I was able to get it right in. They always gave us a little bit of lube to help with ease of insertion and it was great! I didn’t have any issues. I probably could have used it without lube. (Birmingham Participant #2, age 34, Placebo Gel Arm, Female)

Other participants felt more comfortable with having staff administer the initial [and subsequent] gel dosing rather than applying the gel themselves.

“They’re healthcare providers, I’m not. And, knowing me - like if I did it myself - I probably wouldn’t do it correctly, frankly. Just because if I felt something uncomfortable or like some sort of like resistance or something like that, I would probably just squirt it in and it might not get you know absorbed where it needs to be.” (Birmingham Participant #6, age 34, Dapivirine Gel Arm, Male)

Participants overwhelmingly reported not knowing much about the product prior to joining the study. However, after receiving study information during the consent process and instructions prior to insertion, participants felt like they knew more about the product and were more comfortable with the gel. According to one participant who discussed insertion instructions:

“Oh, it’s perfect. I sat there and I read it step by step because I’m an instruction person. I mean so simple, yea, after that I didn’t have to pull the instruction sheet out anymore. And it’s, so I mean that’s what make it so great. I mean, one, two, three, you’re done. Push, done, over. Easy as one, two, three.” (Birmingham Participant #5, age 40, Placebo Gel Arm, Female)

Most participants (96.2%) noted that the gel was easy to use; no differences were observed by study arm ($X_{(1)}^2=0.55$, n.s.), sex assigned at birth or study site (see Table 2). These sentiments were echoed in their IDIs. Frequently, participants described the application process as easy, quick, and painless in their interviews. Several described the overall process as comfortable and straightforward, with simple instructions. More than half of participants referred to the gel application process as easy and expressed that the gel applicator was easy to use in practice. Several participants also noted that the overall process would be easy to do on their own, or that it would be easy for others to do on their own. One participant noted that that the gel applicator would be “discreet and easy” for people to use, disposable, and not painful.

“When the staff inserted the gel, I didn’t even feel that it was already inserted. I might have felt that it was done, but it was done quickly that I didn’t feel anything. I felt that it was easy. Oh, it finished already. It was so quick.” (Thai Participant #18, age 36, Dapivirine Gel Arm, Male)

Additionally, participants expressed several views regarding the applicator’s usability. This included feelings towards the physical applicator, which ranged from liking to disliking the applicator (see Table 2), concerns regarding the applicator’s usability and factors that are believed to possibly increase the usability of the applicator for an individual. Two participants noted a problem inserting the applicator, with both perceiving the applicator tip to be sharp and hurting during insertion. Suggestions regarding the applicator were also echoed during the IDIs:

“I think just by implementing some of the things I was talking about, so like the applicator, I’d put a ridge on it, um just like a couple ridges maybe, just to see like maybe that says like an inch is in, or two inches are in, and you’d feel it because there would be like one or two…. And I think that the tip of the applicator should be changed, I think that should be smoother. And there should be a big hole in it, so like it doesn’t affect like the how, so like the same amount of gel would still come out, …” (Pittsburgh Participant #6, age 21, Placebo Gel Arm, Female)

Notably, many participants commented on the helpfulness of using lubricant to insert the applicator. As such, several suggested that the applicators should be packaged with lubricant already on them, or have lubricant included in the package. In addition, many participants commented that pre-assembling the applicator or setting a specific dosage in the applicator before packaging would aid in consistent usability.

Gel Characteristics & Sensation

When discussing gel characteristics participants focused on its consistency. This is particularly noteworthy, as the viscosity of the DPV gel was approximately 50 times greater than the placebo. In general, participants felt that the gel’s density prevented it from being “runny” or “oozing” out of place.

“I was shocked that it was not thick. I was just shocked at how it is easy and how thin it was. I didn’t feel it. I really think it’s a good product” (Birmingham Participant #5, age 40, Placebo Gel Arm, Female)

Most participants stated that what they liked best about the gel was that they could not tell it was there after they inserted it.

“No. I didn’t touch, I never touched it so I don’t know the consistency of it. It didn’t have a smell to it, didn’t have an odor to it, it didn’t have a color to it. The only thing that I thought was interesting was the urge to expel after insertion.” (Birmingham Participant #2, age 40, Placebo Gel Arm, Female)

Additionally, there were a variety of reactions regarding the sensation participants felt during the administration process. Reactions ranged from “no sensations” to neutral and unrecognizable, with many contributing the overall sensation they felt to the plastic applicator.

“No sensations whatsoever. I didn’t feel, the only thing that I felt was obviously like the plastic tube being like shoved up there, but like, anything past just the plastic tube I didn’t feel a single thing.” (Pittsburgh Participant #1, age 22, Dapivirine Gel Arm, Male)

Considerations for Future Use

When asked whether they would use a rectal gel that provided some protection against HIV in the future, over half of the participants in the study noted that they would prefer the gel over condoms (n = 13; 50%) or that they liked condoms and the gel equally (n = 8; 30.8%). During the interviews, participants discussed several facilitators and barriers when considering using the gel in the future. While there were a wide range of factors discussed related to future use of the study product, categories included were: factors that inhibit use, the effect of partner type and role, and protection against HIV.

Factors that Could Inhibit Use

Participants noted several factors that could potentially inhibit the use of a product like the study gel. While there were a large range of responses, they can be generalized into four themes: unpleasant sensations or side effects, barriers to access, logistical concerns, and individual preferences.

“…For this product also, I think if the product size can be decreased. Something is small and then it can expand. The small size will make it easy to carry with them. If it’s carry with them, then that will encourage adherence. If it’s harder to carry with them, the product would then stay at home. If people who use this study gel get home late, they might be too tired and forget to use the product. Another thing is price. Price is a factor if people would use it every day. If it’s too costly and people need to use the gel consistently, this would make it difficult.” (Thai Participant #19, age 39, Dapivirine Gel Arm, Male)

While many discussed the importance of pre-lubricated tips for insertion, others discussed how pre-assembled packaging could aid in use.

“Not [a] particular recommendation; maybe it can be like an injection where it is pretty much fixed, and there are two components in the packet. It can be just one component, so that they can just remove the cap and just insert the drug.” (Birmingham Participant #3, age 34, Dapivirine Gel Arm, Male)

Factors that Inhibit Use: Side-Effects

Participants reported several side-effects from both the placebo and study gel. Several participants reported anal leakage (n = 8; 30.8%), with events occurring less than 15 min after application (n = 5; 62.5%), between 15 and 29 min after application (n = 2; 25.0%), or more than an hour after application (n = 1; 12.5%). When asked how much the leakage bothered them on a scale from 1 (Not bothered at all) to 10 (Extremely bothered), participants’ median score was 8 (range 1–6). Participants also reported experiencing diarrhea (n = 4; 15.4%), with these events occurring 30–45 min after applying the gel. Another participant also noted that they experienced soiling of their underwear (n = 1; 3.8%) in their surveys and reported being minimally bothered by the event (a score of 2 on the 10-point scale). Most participants mentioned that the side-effect lasted only a short period of time.

“Initially for maybe 10–15 minutes I thought so that it was leaking because after she injected the gel we have to go to some other clinic so meanwhile we were walking and I… I feel that there was some leakage for some minutes, 10, 15, minutes maybe.” (Birmingham Participant #3, age 34, Dapivirine Gel Arm, Male)

Furthermore, while some participants felt physical sensations for a side-effect, others had the unintended consequence of emotional discomfort of being unsure of gel absorption in their body, mentioning timing being too long or the gel not fully absorbing in their body.

“I think it’s just troublesome with the bowel movement. I don’t know how long it would take for the medicine to absorb and takes effect. I can’t really tell. One time after inserting the gel for half an hour, I had a bowel movement like normal, but I felt like the study gel didn’t completely absorb inside yet. The study gel seemed to come out with the stool. After that I time it that I waited around 1 h and a half or 2 h and the study gel did not come out with the stool that way. I feel like it takes too long for the medicine to absorb inside the body.” (Thai Participant #3, age 23, Dapivirine Gel Arm, Male)

The Effect of Partner Type and Role

When asked whether their primary partner would prefer to use a rectal gel that provided some protection against HIV in the future (as compared to condoms), participants had diverse opinions. Apart from those who noted not having a primary partner (n = 6; 23.1%), participants evenly endorsed the gel (n = 6; 23.1%) and the condom (n = 6; 23.1%), or noted that they did not know what their partner would prefer (n = 6; 23.1%). Two participants believed that their primary partner would like condoms and the study gel equally (n = 2; 7.7%). In the interviews, participants expanded on how the potential future use of the gel would be dependent on their partner type, sexual role, and other sex acts apart from anal intercourse. Several participants noted that they thought that receptive partners would be more likely to use the product, with some expressing concern that a rectally administered product may place an undue burden on receptive partners. However, some participants expressed that they would be less likely to use the product with a committed or long-term partner. Similarly, a few participants indicated that they would be more likely to use the product with first time partners or one-time partners.

“No I think (clears throat) that comes down to like how you feel with the person like if I was in a committed relationship I probably wouldn’t use it because I don’t feel the need to if you’re both committed there’s no point on spending money when you’re not gonna get anything. Umm but until like I was at that point like for every hookup, I would use it.” (Birmingham Participant #9, age 20, Dapivirine Gel Arm, Male)

Protection Against HIV

In general, participants felt that HIV prevention is the most important end-goal for inserting the gel and is more important than product design, gel characteristics, or application.

“If I can see the study result that the study gel is actually effective, has no side effects, and the price is affordable, I think I will be likely that I will use it.” (Thai Participant #19, age 39, Dapivirine Gel Arm, Male)

Therefore, an emphasis on marketing from a health standpoint, highlighting HIV prevention benefits, was recommended by participants.

Discussion

Primary findings from the MTN-026 trial determined that DPV rectal gel was well-tolerated and acceptable with DPV plasma concentrations like those of the DPV vaginal ring [29]. However, rectal tissue concentrations were well below vaginal tissue levels following DPV ring use, suggesting that a higher dose would most likely be needed to provide protection from HIV following anal sex [29]. Given these findings, acceptability data are vital to understand what characteristics could pose as a challenge in its reformulation or, alternatively, facilitate its future sustained use as a microbicide gel. To broaden the main trial findings, we employed a mixed-methods analysis to understand participants’ acceptability of and adherence to the rectal gel as a rectal microbicide as a secondary trial endpoint.

Consistent with Morrow and Ruiz’s framework [16], participants’ acceptability aligned with four domains: experiences applying and using the gel, perceived gel characteristics and use-related sensations, perceived side-effects, and considerations for future use. Overall, participants expressed high acceptability to applying and using the DPV and placebo gel. Moreover, most participants reported that they would prefer the gel to male condoms as an HIV prevention method, corroborating prior findings indicating participants’ willingness for other short-term alternatives to HIV prevention. Consistent with prior rectal microbicide research [28, 36], participants’ willingness to use the product in the future was linked to the study gel applicator. While some participants expressed concerns with the application process, most felt that given enough time to learn how to insert and use the applicator it would be easy to incorporate the process into their pre-sex routine. Nevertheless, participants voiced a preference for the study gel to be designed and marketed as a PrEP sexual lubricant. To address this recommendation, the MTN recently completed a trial (MTN-033) which found that the use of the DPV gel as a behaviorally congruent anal lubricant product (i.e., DVP gel as a lubricant administered without needing a rectal applicator) was feasible [37, 38]. Future research is warranted to understand the safety and acceptability of the DPV gel as a sexual lubricant.

Some participants reported skepticism about the study gels prior to using the products, yet most reported willingness to use the study gel after the trial, indicating that they would be willing to use it in the future if it provided some protection against HIV. Most participants did not voice any concerns or perceive that the study gel’s characteristics (e.g., color, scent, thickness) were any different than existing lubricants in the market. While these findings are promising as they signal the potential of real-world acceptability of a DPV gel, participants acknowledged that other considerations (e.g., partners, sexual practices) could hinder their willingness and adoption of the study gel in the future. Consistent with prior research [3, 14, 15, 22, 23, 25, 39], for example, participants acknowledged that experiencing side effects would diminish their enthusiasm for the product. While a few participants ascribed side effects (e.g., leakage, diarrhea) to the study product, these experiences were relatively uncommon across the sample. In most cases, participants found that, if these side-effects were minor, they would be willing to use the gel as a form of HIV prevention. In addition, participants were concerned about logistical concerns tied to the product itself such as its portability, packaging, and need for an applicator. However, we were surprised by participants’ willingness to brainstorm proposed solutions (e.g., pre-assembled or easily assembled plungers, measured dosage, packaging including lubricant, etc.) as part of their interviews. Finally, participants acknowledged that their HIV prevention choice would vary based on their sexual practices and partners. In thinking about whether their primary partner would prefer the gel to a condom, for example, participants expressed diverse opinions. These findings align with prior research [23] highlighting the importance of relationship dynamics in HIV prevention, as well as the need to offer a suite of HIV prevention strategies to key populations.

Several limitations to this study deserve mention. First, given the nature of this Phase I safety trial, we recruited a small sample of low-risk individuals to participate in this study. Individuals living in vulnerable, high-risk contexts may have different needs and perceptions of the rectal gel under study. Second, our sample abstained from receptive anal sexual activity 72 h before and for 7 days after biopsy collection. Therefore, it is difficult to assess how this product might fare in real-world situations prior to receptive anal intercourse. Third, while social desirability may be a potential threat to validity, we tried to minimize social desirability by having participants complete their interviews virtually with non-clinic staff and ensuring that they had a private room where they could answer their CASIs privately. Fourth, our findings regarding the DPV gel may not be generalizable to other microbicide drug candidates. Similarly, given our small sample size, acceptability data cannot be generalized to other populations. Therefore, future research examining DPV gel acceptability and adherence remains vital as new PrEP drugs and devices are tested as potential HIV prevention methods.

Taken together, our findings align with prior RM gel research and support high acceptability of the rectal gels used in this study. Future clinical trials should continue to assess DPV RM gel acceptability among individuals who actively engage in receptive anal intercourse to gain a better understanding of its acceptability. Additional research examining the efficacy and acceptability of DPV RM gel is necessary to further examine and understand the viability of a gel for HIV prevention.