Acceptability of a Rectal Microbicide Douche for HIV Prevention: A Mixed Methods Analysis of a First-in-human Formulation Pilot Study

Abstract

Objectives:

DREAM-01 was an open label, dose-escalation and variable osmolarity study to identify a tenofovir HIV-prevention douche/enema that could achieve protective colon tissue cell concentrations and high acceptability. To assess impact on sexual enjoyment, iso-osmolar and hypo-osmolar placebo douches were provided for at-home use before receptive anal sex (RAS).

Methods:

Eighteen HIV-uninfected men who have RAS were administered three tenofovir douches at the research clinic: Product A, an iso-osmolar dose; Product B, an iso-osmolar escalation dose; and Product C, a hypo-osmolar escalation dose. Following Products A and C, participants were given a saline douche of matching osmolarity to use at home before RAS. Participants reported acceptability via a computer assisted self-interview and in-depth interview in this mixed-methods study.

Results:

All three products were rated acceptable by seventeen (95%) of the participants. A majority (94%) would be likely or very likely to use any of the three products before RAS. Of those who used the saline douches before RAS and then rated their sexual enjoyment, most reported that their sexual enjoyment was not affected. Interview data revealed that participants found the product easy to incorporate into their regular routine, but would prefer to use more liquid for cleansing.

Conclusions:

These findings indicate that the hypo-osmolar Product C, which also provides the most rapid delivery of tenofovir for HIV prevention, is acceptable for future safety trials and that our sample reports high likelihood of using a rectal microbicide douche for HIV prevention. Our findings support continued pursuit of a tenofovir rectal microbicide douche.

Introduction

Although oral and injectable HIV pre-exposure prophylaxis (PrEP) have been approved, no topical on-demand options exist for receptive anal sex (RAS). On-demand, topical PrEP is ideal for those who have occasional unprotected sex or prefer a non-systemic product. Throughout PrEP development, potential users have requested a topical product that can be incorporated into existing behaviors without interfering with pleasure.^1–5 Hence, an on-demand, topical option may help increase PrEP uptake, currently insufficient to curb the epidemic.⁶

Men who have receptive anal sex (RAS) often use rectal douches for hygiene. Among men who reported RAS in the US, 88% had ever douched, with at least half douching recently, mostly prior to RAS.⁷ An international survey of 5,127 sexual minority men from 52 countries in Africa and the Americas⁸ found that, among those reporting RAS, 80% in the US, 73% in Africa, and 63% in Latin America douched beforehand. Furthermore, 98% of those who douched and 96% of those who did not would be likely to use a rectal douche for HIV prevention, making a rectal microbicide douche a welcomed behaviorally congruent on-demand product.

Previous clinical studies indicated two different hyper-osmolar tenofovir gels were not acceptable for rectal use due largely to gastrointestinal side effects.^9,10 Subsequently, a douche formulation of tenofovir with lower osmolality was developed. DREAM-01 studied the safety, pharmacokinetics (PK), pharmacodynamics (PD), and acceptability of these lower osmolality products. The safety and PK/PD results of DREAM-01 have been previously reported.¹¹ Here, we detail the DREAM-01 behavioral aims to assess the acceptability of the three study products administered in the research unit and two types of douches used at home in the context of RAS to richly complement the PK/PD data to inform further clinical development of this topical, on-demand rectal microbicide douche.

Methods

Study Design

DREAM-01 was a first-in-human pilot study of three distinct TFV microbicides formulated as a 125 mL cleansing rectal douche and administered sequentially in a single ascending dose design. Product A (220mg TFV, iso-osmolar), Product B (660mg TFV iso-osmolar), and Product C (660mg TFV, hypo-osmolar) were dosed sequentially with a washout period in between if the prior product met safety and acceptability criteria. This manuscript reports the behavioral aim to determine the acceptability of each of the three rectal douches. We used mixed-methods to assess the behavioral aims. Also, the study was designed with community input from the International Rectal Microbicide Advocates.

Study Setting and Participants

Participants (n=18) were HIV-uninfected men with a history of consensual RAS at least five times in their life and once in the past three months who had used a rectal douche within the prior year. They were recruited from research center registries and via flyers/social media ads. They were enrolled at three study sites (in Baltimore, Pittsburgh, and Los Angeles) between November 2016 and November 2017 and all completed the study by July 2018. The study was reviewed and approved by Institutional Review Boards at each of the participating study sites (Johns Hopkins University, the University of Pittsburgh, and the University of California at Los Angeles), and at the New York State Psychiatric Institute (IRB Protocol #7308), where the behavioral team was based. All participants signed informed consent prior to participation and were compensated based on study procedures completed.

Study Procedures

At baseline, participants completed a web-based computer assisted self-interview (CASI) behavioral questionnaire exploring demographics, regular sexual practices, douching behaviors, and likelihood of using a rectal microbicide douche. Subsequently, a site investigator administered a single dose of Product A, which was followed closely thereafter by participant completion of a CASI Research Unit Dose Acceptability Questionnaire in-clinic. Participants were then instructed to take home and use one dose of a 120 mL normal saline douche (a placebo with similar osmolality as Product A) within one hour before engaging in RAS over the next 30 days. Two extra doses were provided so participants could try the product on another occasion if sex did not follow the initial douche. After each dose, participants completed the web-based CASI Take-Home Dose Acceptability Questionnaire.

Participants returned to the clinic within 30 days and were administered a dose of Product B and completed a second Research Unit Dose Acceptability Questionnaire, with no take home doses due to similar osmolality as Product A.

Finally, participants were administered a dose of Product C and completed a final Research Unit Dose Acceptability Questionnaire. They were given a 120 mL half-normal saline douche (similar osmolality as Product C) to use at home, with two extra doses. After each dose, participants completed the Take-Home Dose Acceptability Questionnaire.

After using all products, participants completed an in-depth interview to explore their experiences. The order of product use was not randomized by necessity as each phase of the study depended on safety data from the previous phase.

Behavioral Assessments

Baseline Behavioral Questionnaire

Participants were asked to self-report age, race, ethnicity, and sexual identity; RAS frequency and condom use in the past three months; rectal douche use in the past three months and regular frequency; and future likelihood of using of a microbicide douche for HIV prevention before RAS.

Research Unit Dose Acceptability Questionnaire

Participants rated the acceptability of study products administered in-clinic along several domains: overall liking or disliking; likelihood of using for HIV prevention before RAS; confidence in feeling clean after one dose; number of extra doses needed if not completely confident; and willingness to use a douche with double or half the volume of liquid.

Take-Home Douche Acceptability Questionnaire

Participants reported on acceptability and sexual enjoyment for each take-home douche.

In-depth Interview

Participants were asked in detail about reasons for product ratings indicated in the questionnaires, product use with RAS, and future likelihood of using the product. The interview guide is included in Supplementary Materials (See Supplementary 1).

CASI questionnaires were administered in a private space and in-depth interviews took place with a trained off-site interviewer via phone to reduce response and social desirability biases and lasted on average 26 minutes.

Data Analysis

Quantitative analyses were primarily descriptive, showing acceptability and reaction ratings for each product. Futility tests to identify non-acceptable products were also conducted, with acceptability defined as a mean of 3 or higher on 4-point acceptability measures.¹²

Interviews were audio-recorded, transcribed, cleaned, and uploaded to NVivo for coding. Data were coded independently by two researchers (RG and CL), using manifest content analysis. A codebook was developed based on the semi-structured interview guide, with inclusion and exclusion criteria. Researchers discussed and reconciled coding for each transcript, modifying the codebook as necessary. Each coding report was summarized by the researchers and reviewed by a third researcher (ACD) for content and clarity.

Results

CASI Questionnaires

Participant Demographics and Sexual Behavior

There were 18 participants enrolled at all three study sites (7 in Baltimore, 8 in Pittsburgh, and 3 in Los Angeles) who received all three products and completed all behavioral assessments. Participants’ average age was 42 years. Most were White, non-Hispanic, and self-identified as gay. In the three months prior to baseline, participants reported an average of four RAS occasions; half were unprotected with one partner. (See Table 1)

Table 1.

Baseline Characteristics (n = 18)

	n (%)	M (SD)	Median	Range
Age	18	41.94 (11.84)	40.50	24 – 61
Racea
Black/African American	3 (17%)
White	13 (72%)
Asian	1 (6%)
American Indian/Alaska Native	1 (6%)
Other (“Chicano”)	1 (6%)
Ethnicity
Hispanic	3 (17%)
Sexual Identity
Gay	16 (89%)
Bisexual	2 (11%)
# of RAI occasions (past 3 months)	18	4.28 (4.74)	3.00	0 – 18
Unprotected RAI occasions	18	2.06 (2.82)	1.00	0 – 10
# of URAI partners	18	0.78 (1.00)	1.00	0 – 4
# of times douched (past 3 months)	18	5.28 (5.53)	3.50	0 – 20

Note. RAI: receptive anal intercourse.

^aSelect all that apply; one participant selected American Indian and White.

History of Rectal Douche Use at Baseline

Sixteen participants (89%) reported using a rectal douche at least once in the prior three months at baseline; five (28%) used douches ten or more times. Range of use varied from once to 20 times. Thirteen participants (72%) used douches in preparation for sex, eight of whom (44%) reported doing so always or frequently. (See Table 1)

Baseline Likelihood of Rectal Microbicide Douche Use

A majority of the participants rated themselves as very likely (n=9, 53%) or likely (n=6, 35%) to use a rectal microbicide douche. Two rated themselves unlikely to use it, and one declined to answer.

Research Unit Dose Acceptability

For seventeen (95%) of the participants, ratings for Products A (iso-osmolar, TFV 220 mg), B (iso-osmolar, TFV 660 mg), and C (hypo-osmolar, TFV 660 mg) were highly or somewhat acceptable. Mean acceptability ratings were similar for all three products (See Table 2). Over half of the participants reported liking the products, while the rest gave neutral ratings, with only one negative rating (for Product B). After trying each study product in clinic, a vast majority (94%) reported being likely or very likely to use any of the three products before RAS. A majority were also likely to use the products after RAS, or even both before and after RAS. (See Table 2)

Table 2.

Acceptability, Liking, and Likelihood of Use in the Context of RAS of Study Products Used in Clinic

	Product A	Product B	Product C
	N (%)	N (%)	N (%)
Product Acceptability a
Highly acceptable	16 (89%)	16 (89%)	14 (78%)
Somewhat acceptable	1 (6%)	1 (6%)	3 (17%)
Somewhat unacceptable	0 (0%)	1 (6%)	0 (0%)
Completely unacceptable	1 (6%)	0 (0%)	1 (6%)
Liking the Product b
Liked very much	5 (28%)	6 (33%)	6 (33%)
Liked a little	5 (28%)	4 (22%)	4 (22%)
Neither liked nor disliked	8 (44%)	7 (39%)	8 (44%)
Disliked a little	0 (0%)	0 (0%)	0 (0%)
Disliked very much	0 (0%)	1 (6%)	0 (0%)
Proportion Likely to Use Product in the Context of RAS
Before & After	15 (83%)	11 (61%)	11 (61%)
Before only	17 (94%)	17 (94%)	16 (94%)
After only	12 (67%)	9 (50%)	11 (61%)

^aOn a scale of 1–4, where 1 = completely unacceptable and 4 = highly acceptable

^bOn a scale of 1–5, where 1 = disliked very much and 5 = liked very much

Cleanliness after Study Product Use

For Product A, six participants reported feeling completely confident, six reported feeling somewhat confident, and six reported feeling not at all confident that one dose of the study douche would clean their rectum satisfactorily. For Product B, three reported feeling completely confident, ten somewhat confident, and five not at all confident that one dose would cleanse them to their satisfaction. Finally, for Product C, three reported feeling completely confident, nine somewhat confident, and six not at all confident that one dose would cleanse their rectum. On average, participants reported needing 1.7 extra doses to feel clean.

Take-Home Douche Use and Sexual Enjoyment

Participants who used the two take-home products before RAS were asked about effects on sexual enjoyment. Of thirteen participants who used the normal saline douche before RAS, two (15%) reported more sexual enjoyment than usual, ten (77%) reported sexual enjoyment was not affected, and one reported less sexual enjoyment than usual. All ten participants who used the half-normal saline douche before RAS reported that their sexual enjoyment was not affected. (See Table 3)

Table 3.

Effect on Sexual Pleasure of Take-Home Products

	More than usual	Not affected at all	Less than usual
	N (%)	N (%)	N (%)
Normal Salinec	2 (15%)	10 (77%)	1 (8%)
Half-normal Salined		10 (100%)

^cSimilar osmolality to Products A and B, used before RAS by 13 people

^dSimilar osmolality to Product C, used before RAS by 10 people

A majority (94%, n=17)) used at least one of the take home douches within an hour of RAS, reporting that this process usually went smoothly. Only one was unable to use the study product within the context of RAS; he did not provide a reason during his interview.

In-depth Interview Findings

Reasons for Acceptability Ratings

Some reported liking the product because it was easy and convenient. Others, simply because it worked to help them feel clean before sex and they had no issues. Among users whose acceptability ratings increased from one product to the next, the primary reason cited was increased comfort and familiarity with use.

Lower acceptability ratings were due to side effects (e.g., bloating, prolonged gas, looser bowel movements, dryness), insufficient cleanliness after use. Several participants who used the take-home douche in preparation for RAS reported that one administration usually wasn’t sufficient to leave them feeling as clean as desired. They mitigated this challenge via additional douching applications, supplementing the study product with other douching products (e.g., Fleet^® enema solution, water), and disclosing product use to partners to warn them about a potential decrease in cleanliness.

“I think what I based it on was two things. Did I feel clean after using it. And did I have prolonged gas – you know, bloating… I think I’ve indicated that, but I think with the second one [gave a lower rating], I had excessive bloating, and gas, and you don’t feel attractive when you feel like that.” (African-American, Bisexual-identified, Baltimore)

Another factor that reduced acceptability was difficulty with the douching bottle.

“The most difficult was the bottle, the squeezing of the fluid into the rectum. The bottle seems to be very stiff, and when you get to the last – to the bottom of the fluid, you actually have to roll the bottle, squish it and roll it to get the excess out of the bottle. And that seemed to be very difficult.” (White, Gay-identified, Baltimore)

Product Use with RAS

Ability to anticipate sexual encounters and integrate douching into pre-sex preparations facilitated use of the product.

“If we were going to do something, because I knew it was meant for receptive anal intercourse, I would do it ahead of time, like, within maybe the half hour. So, I would go into the bathroom, you know, and cleanse, and use it. I’d wait, and I’d time myself with my iPhone, so I knew when five minutes was up, and then I would clean.” (White, Gay-identified, Pittsburgh)

A few reported using the product after RAS, either because their encounters were spontaneous or they preferred to integrate douching into their post-sex bathing rituals. Of those who used it before RAS, a few reported difficulty integrating it into the sexual encounter, either because they were pressed for time or felt awkward interrupting the encounter to go “clean.”

“Yeah, I guess the trickiest part, I would say, was having used it within an hour, you know, having receptive sex within the hour of doing the douches. That was tricky. You know, just because, like, ‘Oh, if I do it, ‘I’ve got to rush!’” White, Gay-identified, Baltimore)

Most participants who used it before RAS reported no impact on their enjoyment or pleasure. Of those who disclosed product use to partners, many reported that their partners were supportive; one even stated that his partner helped him with the douche administration process.

“I would use that with my partner, and like, when we – yeah, administering at least the take-home douches before RAS, like, he helped me do it, and it was just sort of this like, oh, you know, we’re doing this thing, cool. Like, probably going to improve our sexual experience, and like, it’s a little bit weird, but it’s also – not weird whatsoever, and just like a good thing to be doing as partners.” (White, Gay-identified, Pittsburgh)

Likelihood of Use in the Future

Most felt very positively about the concept. Some could envision themselves using it in conjunction with other forms of protection, such as condoms, to protect against STIs other than HIV. A few noted that they’d prefer a rectal microbicide douche over the existing HIV protection options.

“I would prefer that.. I feel like it’s a little more efficient. And, you know, it’s doing its thing while I’m engaging in sex. So I don’t really have to worry about, you know, the condom rupturing or breaking – I have anxiety associated with that, so – I like just getting the full experience of sex without having to worry about a bunch of barriers that are impeding the pleasure.” (White, Gay-identified, Baltimore)

In addition to protection, a few liked the idea of a microbicide douche for hygienic reasons. Many thought using a microbicide douche every time they engage in RAS would be easy, requiring little to no planning prior to the sexual encounter, because douching was already a part of their pre-sex ritual.

“Oh, I do it anyway, so it’s a part of our routine… it’s proper for me. (laughs) It’s like washing my hands before I eat.” (African-American, Bisexual-identified, Baltimore)

Nevertheless, many clarified that they would be more likely to use a microbicide douche if they could apply it directly after a cleansing douche and preferred to use it routinely before RAS but were willing to consider douching after sex.

Discussion

Based on DREAM-01 behavioral data, all three products were acceptable to participants, as mean ratings were well above 3. Ninety-five percent of participants rated all three products somewhat or highly acceptable, including those who were unlikely to use a rectal microbicide douche at baseline, which demonstrates that experience with the douche can improve acceptability and likelihood of use. Overall, a vast majority were enthusiastic about using a rectal microbicide douche before RAS for HIV prevention once they had tried it.

The findings from each phase of the study informed the design of subsequent DREAM studies. For example, many DREAM-01 participants reported needing more than the 125 mL dose to feel clean, and some used a water douche to ensure cleanliness. To address issues of cleanliness and volume, the DREAM-03 study examined distribution of the microbicide douche when used before or after a water douche compared to multiple sequential microbicide douches.¹³

In addition, as several participants complained about difficulties squeezing all of the liquid out of the provided bottle, preferring to use their own douching apparatus, the study team developed a powder formulation that could be mixed with water and used with a variety of applicators.¹⁴

DREAM-04 examined whether participants were able to mix and prepare the tenofovir douche using the provided sachets.

DREAM-01 was the first bio-behavioral study to develop a rectal microbicide douche and test its acceptability among potential end-users. Since then, other studies have continued to investigate the demand for and acceptability of a rectal microbicide douche among sexual minority men. One study that examined rectal douching behaviors found that douching was more common among racial/ethnic minorities and those who had recently tested for HIV.¹⁵ Participants who douched more frequently endorsed higher acceptability for a rectal microbicide, suggesting that a behaviorally congruent formulation such as a rectal microbicide douche could be important for this community.¹⁵

An international study of three placebo rectal microbicide formulations revealed that participants found a rectal douche highly acceptable and they were able to be highly adherent to use before RAS.¹⁶ Among the international sample from the US, Peru, Thailand, South Africa, and Malawi, a majority of participants from the US, Peru and nearly half in South Africa selected the douche as their most preferred out of three products (compared to an insert and a suppository).¹⁷ Experience with rectal douches was significantly associated with preference for the douche, again demonstrating the desire for a behaviorally congruent product among this population.

Similarly, a conjoint experiment in the US comparing interest in daily oral PrEP, event-driven PrEP, event-driven rectal douches, injections, infusions, and implants for HIV prevention found that a rectal douche was preferred by those who wanted to be able to stop using a microbicide at any time.¹⁸ Finally, an international discrete choice experiment comparing daily pills, event-driven pills, injections, implants, and rectal douches found that the rectal douche was the second most popular modality among participants in the US and South Africa.¹⁹ Therefore, research on rectal microbicides continues to indicate that a douche formulation would be likely to be used and acceptable to sexual minority men.

In addition, the DREAM study findings directly informed the design of HPTN 106, a phase 2 study comparing event-driven oral pills to an event-driven rectal douche for HIV prevention that is in the startup phase.²⁰ HPTN 106 is using a TFV granule sachet and dosing scheme based upon results from this DREAM-01 behavioral analysis and subsequent DREAM Program studies (DREAM-03, DREAM-04) described above.

Our study had noteworthy limitations. First, a small US-based sample is insufficient to generalize findings. Second, due to regulatory limitations, we could not provide participants with the microbicide douche to use in the context of RAS, so impact on sexual enjoyment is based on placebo douches with similar NaCl-dependent osmolarity. Third, the study recruited men who were interested in HIV prevention studies, so opinions on study products may be biased. In addition, the order of product use was not randomized by necessity due to each phase depending on safety data from the previous phase. This could have biased participants by allowing them to become familiar with the product use regimen and overcome any obstacles so that acceptability could have been higher for the third product. Nevertheless, the study revealed interest in and acceptability of a highly efficient rectal microbicide douche, providing proof of concept for moving forward and useful lessons for future product design, trial design, and research participant messaging.

In summary, DREAM-01 found that a rectal microbicide douche is acceptable, likely to be used for HIV prevention, and unlikely to impact sexual enjoyment. These findings provide evidence for continued pursuit of a behaviorally congruent rectal microbicide douche.

Key messages.

What is already known on this topic:

Although oral and injectable PrEP now exist on the market, sexual minority men still do not have any topical on-demand HIV prevention options besides condoms. Given that rectal douching is commonly employed to ensure cleanliness prior to receptive anal sex, a rectal microbicide douche could increase uptake of PrEP, especially among people who do not want a systemic product or only have occasional unprotected sexual encounters.

What this study adds:

The DREAM-01 study found three tenofovir douche formulations acceptable and likely to be used for on demand PrEP. These findings provide further proof of concept for continued development for later phase clinical trials.

How this study might affect research, practice, or policy:

Our findings indicate that continued development of an on demand, behaviorally-congruent rectal microbicide douche is warranted. The products were acceptable, likely to be used, and did not negatively impact sexual enjoyment.