Acceptability of an extended duration vaginal ring for HIV prevention and interest in a multi-purpose ring.

Given challenges with adherence to existing HIV prevention products, the development of an extended duration vaginal ring could improve adherence while reducing patient and provider burden. Additionally, women have other interlinked sexual health concerns such as unintended pregnancy. We evaluated acceptability of a 90-day ring to prevent HIV and hypothetical preferences for a dual (HIV and contraceptive) indication. This was a secondary analysis of a Phase 1, two-arm, multi-site, placebo-controlled randomized trial evaluating safety and pharmacokinetics of a 90-day vaginal ring containing tenofovir for HIV prevention (N = 49). We used a mixed methods approach to assess quantitative data on acceptability (n = 49) and used qualitative data from a random subset to explain the quantitative findings (N = 25). The 3-month extended duration tenofovir ring was highly acceptable. Participants perceived the ring to be easy to use, comfortable and reported liking it more over time. About half felt the ring during sex but most of those participants said it bothered them only a little. Concerns about hygiene increased over the study period but were often outweighed by the benefits of an extended duration ring. Interest in a multi-purpose ring was high (77%) and even higher among those who were sexually active and had male partners. The 3-month extended duration tenofovir ring for HIV prevention was highly acceptable among women and interest in an MPT was high.

Introduction

Women represent 48% of new human immunodeficiency (HIV) infections occurring worldwide [1]. Given the high burden in women, there is a need to develop effective and acceptable biomedical interventions to prevent HIV. Clinical trials support safety and tolerability of tenofovir (TFV) for the prevention of HIV acquisition, specifically in vaginal gel [2-4] and oral tablet formulations [5]. However, adherence has been a significant barrier to the effective use of these products, particularly among young women (age 15–24) [2, 3, 5–7]. Similarly, two phase III HIV-1 prevention trials using the dapivirine (DPV) vaginal ring reported a significant reduction in HIV-1 incidence but women under 21 years old achieved less protective benefit from the DPV ring due to low adherence [8, 9]. Given these challenges, women may benefit from increased choices in HIV prevention products to identify one that is best suited for their needs. The development of an extended duration (90 day) vaginal ring may allow less frequent ring replacements (i.e., quarterly instead of monthly) thus may improve product adherence and reduce patient and provider burden.

Additionally, women have other simultaneous and interlinked sexual health concerns such as acquisition of other sexually transmitted infections (STI) like herpes simplex virus type 2 (HSV-2), which can increase risk of HIV-1 infection [10-12], and unintended pregnancy. Multi-purpose prevention technologies (MPTs) are products that offer protection against multiple outcomes, such as multiple STIs (e.g., HSV-2 and HIV-1) or unintended pregnancy, with the use of a single product. There is a need to assess interest and preferences for an MPT among women to inform the development of these products.

The MTN-038 trial was a collaboration between the Microbicide Trials Network (MTN) and CONRAD, a not-for-profit research organization that developed the tenofovir vaginal ring, to evaluate the pharmacokinetics and safety of an extended duration (90 day) tenofovir ring, as compared to a placebo ring. We used data from MTN-038 to describe acceptability of a three-month vaginal ring (placebo versus tenofovir) for HIV prevention and hypothetical preferences for an MPT product using a mixed methods approach. While previous research has evaluated acceptability of a one-month ring, we add to the literature by describing acceptability of a three-month tenofovir ring. Specifically, our objectives were to: 1) evaluate components of acceptability of the ring used continuously for 91 days to prevent HIV in women living in three cities in the United States; and 2) understand interest/preference in a single (HIV prevention) vs. dual-purpose (contraceptive and HIV prevention) indication.

Materials and methods

Study population

We used quantitative and qualitative data from people who participated in the MTN-038 trial in Birmingham, AL, San Francisco, CA, and Pittsburgh, PA, between January 2019 and August 2019 to assess acceptability of the extended duration (90 day) tenofovir ring and preferences for an MPT ring. MTN-038 was a Phase 1, randomized-controlled trial to evaluate pharmacokinetics and safety of a 90-day 1.4-gram tenofovir vaginal ring to prevent HIV. The 1.4 g TFV ring consists of a drug-loaded hydrophilic polyether urethane tube (white segment) that is sealed and joined together (transparent joint) to form the shape of a ring. This is a reservoir ring using a water-absorbable polyurethane as a rate controlling membrane which can deliver approximately 10 mg/day TFV for 90 days (Fig 1). The TFV IVR has a 0.7 mm wall thickness, 5.5 mm outer cross-sectional diameter and 55 mm outer diameter. The dapivirine ring is slightly different and is a silicone polymer matrix-type ring with a cross-sectional diameter of 7.7 mm and outer diameter of 56 mm. A comparison of rings is available on the MTN 038 website [13]. The study enrolled 49 healthy, HIV-uninfected individuals assigned female sex at birth (inclusive of transgender men and nonbinary people), who were 18–45 years old. Sample size calculations were based upon the size of similar Phase 1 studies of vaginal microbicide products and focused on the primary endpoints of safety and pharmacokinetics of the ring. Assuming a standard deviation of 2.4. the acceptability score from a prior study, we estimated the study would have 90% power to detect a difference in the acceptability score of 2.65 with 32 participants [14]. Additional detail on sample size calculations will be available in the primary publication from the study evaluating safety and pharmacokinetics of the ring (Microbide Trials Network 038 study, 2021) [15]. All participants were required to be using an effective method of contraception (hormonal methods, intrauterine device, sterilization, sex exclusively with individuals assigned female sex at birth, or sexually abstinent) for at least 30 days prior to enrollment and intending to continue use of an effective method for the duration of study participation. Participants were randomized 2:1 to receive either the tenofovir ring or a matching placebo ring and were instructed to use the ring continuously for 91 days, including during menses. Participants in the trial were instructed not to remove the ring for 90 days after insertion including during menses, to clean it, or for intercourse. Participants were not told their group assignment to minimize bias in self-reported measures. Prior participation in other ring trials was allowed and 19 participants previously participated in MTN-036/IPM 047, a Phase 1, randomized, three-arm, open label trial that compared a 1-month vaginal ring containing 25mg to a 3-month vaginal ring containing 100mg or 200mg of dapivirine (DPV) and was conducted in Birmingham, AL and San Francisco, CA between November 2017 and January 2019.

Fig 1

CONRAD 90-day 1.4-gram tenofovir vaginal ring to prevent HIV used in the MTN 038 study.

Procedures and measures

Quantitative

We collected quantitative behavioral data via computer-assisted self-interview (CASI) at enrollment, and then approximately monthly at day 28, day 56, and day 91 or product use end visit (PUEV). We assessed acceptability at day 28 and PUEV, with a more thorough questionnaire administered at PUEV. Acceptability questions were derived from an acceptability framework [16] and included participant’s attitude related to the ring (ring characteristics; likes and dislikes concerning the ring), her experiences using the ring (e.g., genitourinary discomfort, ease of use/removal, willingness to use during menstruation, willingness to use in the future), and effect on sex. We assessed HIV prevention versus MPT preference only at PUEV. Other topics in the behavioral assessment were participant demographics, motivation to join the trial, vaginal and sexual practices, study product adherence, and sexual partners. All measures were used previously in MTN-036 and other microbicide trials [14, 17, 18].

We used the measures listed in Table 1 to assess components of acceptability for the extended duration ring, and ring preferences. Response options were on a 4–5 point Likert scale unless otherwise noted. All questions were asked in relation to the time period since the start of the study. For the second research objective, we assessed preference for HIV prevention vs. an MPT ring using the question “Would you be more likely to use a ring for HIV prevention if it could also prevent pregnancy (a dual-purpose ring)?” (Yes/No-equally likely/No-less likely to use MPT). Characteristics evaluated in relation to MPT preference included sociodemographic variables (e.g. age, education, contraceptive use), geographical site, sexual partners and activity.

Table 1

Selected quantitative measures of acceptability and preference.

Domain	Measure*	Response options	Timepoint
Acceptability	Overall, how much do you like the ring?	10-point Likert scale	Day 28 & Day 91/PUEV
		1 = Extremely Dislike, 5 = Neutral, 10 = Extremely Like
	How do you like the ring now compared to when you started the study?	I like it MORE now,	Day 28 & Day 91/PUEV
		I like it LESS now,
		I like it the SAME,
		I do not like the ring
	How did it feel to have the ring inside you every day?	Very comfortable, comfortable,	Day 28 & Day 91/PUEV
		uncomfortable, very uncomfortable
	How easy or difficult was it to use the ring?	Very difficult, difficult, easy, very easy	Day 28 & Day 91/PUEV
	Were you aware of the ring during your normal daily activities?	Never, some of the time, most of the time, all of the time	Day 28 & Day 91/PUEV
	Have you noticed any of the following changes in your vagina while wearing the ring? • Vagina was wetter • Vagina was drier • Your vagina had a change in odor or scent	Yes, no	Day 28 & Day 91/PUEV
		Not at all, a little, somewhat, very much
	How much has the change bothered you?
	How worried are you about the ring being dirty or unhygienic?	Not at all, a little, somewhat, very much	Day 28 & Day 91/PUEV
	How worried are you about the ring causing infection, infertility, or other long term health problems?	Not at all, a little, somewhat, very much	Day 28 & Day 91/PUEV
	How much did it bother you to wear the ring during menses?	10-point Likert scale	Day 28 & Day 91/PUEV
		1 = Not at all,10 = Very much
	How often did you feel the ring inside you when you had sex?	Never, some of the time, most of the time, all of the time,	Day 28 & Day 91/PUEV
	How much did it bother you?	I never had sex with the ring in
		Not at all, a little, somewhat, very much
Preferences	Which would you prefer: a ring that can be worn for three months and then replaced with a new one, or one that must be replaced with a new one every month?	Prefer 3 months,	Day 91/PUEV
		Prefer 1 month,
		No preference
	Which would you prefer: a ring that you leave in continuously, or a ring that you insert only on the days when you have sex?	Prefer leaving in continuously,	Day 91/PUEV
		Prefer inserting only when I have sex,
		No preference
	Which do you think your primary partner would prefer as a method to prevent HIV?	Ring,	Day 91/PUEV
		Condom,
		PrEP (daily oral pill),
		Don’t know,
		N/A—no partner

* all questions were asked in relation to the time period since the start of the study

Qualitative

A subset of 25 participants were randomly selected to complete an in-depth interview (IDI) before exiting from the trial. IDIs were conducted by one of three trained, female, qualitative interviewers using a semi-structured questionnaire guide. Interviews were conducted over the computer via video call and lasted approximately 60 minutes. Topics assessed were: challenges using study products, specifically in relation to hygiene, menses and sex; perceived benefits and barriers to ring use; and perceived method(s) preferences for HIV prevention and MPTs. Interviewers engaged in peer debriefing sessions regularly throughout the data collection period to critically reflect on interviewing techniques. All IDIs were audio recorded and transcribed by an external transcription agency, with transcripts reviewed for quality by interviewers and qualitative analysts before coding and analysis.

Analysis

First, we compared differences between the placebo and active ring in overall acceptability to determine if study arms could be combined. Overall acceptability was measured on a ten-point Likert scale and differences were tested using a Wilcoxon rank-sum test. We identified no significant differences by arm, and therefore all acceptability analyses used aggregate data combining the study arms. Second, we used descriptive statistics to summarize sociodemographic characteristics and sexual behavior of the study participants at baseline. For categorical variables, we reported the number and percentage in each category; for continuous variables, the mean, median, standard deviation, quartiles and range (minimum, maximum). Next, we described measures of acceptability at enrollment and at each study visit. Preferences were described only at the last visit. Differences by characteristics were assessed using Chi-squared or Fisher’s exact tests. Changes in outcomes were assessed over time using Poisson regression to estimate a relative risk with robust standard errors (for binary) [19] or linear regression (for continuous). We accounted for repeated measures within participants using generalized estimating equations (GEE) [20]. Lastly, we described preferences for an MPT ring overall and by the participant characteristics using descriptive statistics and tested for differences using Chi-squared or Fisher’s exact tests. We used an alpha of 0.05 to determine statistical significance. Characteristics included age, study site, whether the participant had menses while using the ring, and whether (or how much) she engaged in penile-vaginal intercourse while using the ring, as well as prior history with vaginal products and contraceptive use. Prior history of vaginal products was defined as use of the NuvaRing, Estring, Femring or prior participant in trial of vaginal ring. Use of Estring and Femring were unlikely in this premenopausal population but were included to capture even the small chance of prior use. All analyses were done with Stata version 16 (16.1, StataCorp LLC, College Station, TX).

Qualitative data were analyzed to further explain key quantitative findings. We used an existing codebook that was previously developed and applied to qualitative data in a similar trial [17]. Transcripts were coded using Dedoose software v7.0.23 by a team of two analysts who met regularly during the coding process to discuss findings and intercoder discrepancies. For this analysis, we examined code reports related to acceptability and MPT interest. This included the following codes: MPT, ATTITUDES, PROS/CONS, SEX, SIDE EFFECTS, and HEALTH. Code report excerpts were organized by participant to summarize data. Summary memos were then written, identifying themes and interpreting findings.

Ethical statement

The MTN-038 study protocol was approved by the Institutional Review Board at each study site and was overseen by the regulatory branch of the Division of AIDS (DAIDS) and MTN. All participants provided written informed consent prior to study participation and IDI participants provided further verbal consent before being interviewed.

Results

Characteristics of the 49 participants included in this analysis are described in Table 2. The median age was 29 years with 29% under 25. Nearly 60% (n = 28) had only male sex partners in the past year; 14% (n = 7) had both male and female sex partners, and 10% (n = 5) had only female partners. Half (n = 24) had prior experience using a vaginal ring, mostly from prior participation in another vaginal ring trial (MTN-036, n = 19). Two participants (4%) did not complete all follow-up.

Table 2

Characteristics of participants enrolled in MTN-038, a Phase 1, randomized-controlled trial to evaluate a 90-day 1.4-gram tenofovir vaginal ring (N = 49).

	N	%
Age - median (range)	29	(18–43)
18–24	14	(29)
Race1
White	31	(63)
Black or African American	15	(31)
Asian	6	(12)
Graduated from college	32	(65)
Hispanic or Latinx	3	(6)
Sexual history & orientation
Biological sex of vaginal sex partner(s) in past year
Exclusively male	28	(57)
Exclusively female	5	(10)
Both male and female	7	(14)
No vaginal sex in past year2	9	(18)
Vaginal practices & products ever used
Prior use of a vaginal ring3	24	(49)
Current contraceptive method
IUD	16	(33)
Oral pill	12	(24)
Injectable	4	(8)
Implant	3	(6)
None	14	(29)

1 multiple responses allowed

2 identify as: heterosexual (N = 6), bisexual (N = 3)

3 such as NuvaRing, Estring, Femring (N = 12) or prior participant in trial of vaginal ring (N = 19)

4 one participant missed the day-28 visit and another missed PUEV

General acceptability

At study exit (n = 48), the median acceptability rating was 8 out of 10 (interquartile range, [IQR] 7–9). All other acceptability outcomes are presented in Table 3. Nearly all participants found the ring easy to use (98%, n = 47) and comfortable (96%; n = 46), and most were never aware of the ring during normal daily activities (75%, n = 36). After 28 days of use, 23% (n = 11) of participants indicated they liked the ring more than at enrollment, and the average overall acceptability improved by 1.2 points (95% CI: 0.7, 1.8; p<0.001).

Table 3

Measures of acceptability collected via CASI among participants enrolled in MTN-038 (N = 48).

	Day 28		Day 91/PUEV
Acceptability measures	N	%	N	%
Total	48	(100)	48	(100)
Overall, how much do you like the ring? (score 1–10: Extremely like)
Median (IQR)	8.5	(5–10)	8	(7–9)
How do you like the ring now compared to when you started the study?
I like it MORE now	11	(23)	18	(38)
I like it LESS now	3	(6)	1	(2)
I like it the SAME	34	(71)	28	(58)
I do not like the ring	0	(0)	1	(2)
How did it feel to have the ring inside you every day?
Very comfortable/comfortable	44	(92)	46	(96)
Uncomfortable/very uncomfortable	4	(8)	2	(4)
How easy or difficult was it to use the ring?
Very easy/easy	47	(98)	47	(98)
Difficult/very difficult	1	(2)	1	(2)
Were you aware of the ring during your normal daily activities?
Never	39	(81)	36	(75)
Most/some of the time	9	(19)	12	(25)
Have you noticed the following changes in your vagina while wearing the ring?
Vagina was wetter	24	(50)	23	(48)
How much did that bother you?—Not at all	13	(27)	12	(25)
A little/somewhat	11	(23)	11	(23)
Vagina was drier	4	(8)	2	(4)
How much did that bother you?—Not at all	0	(0)	0	(0)
A little/somewhat	4	(8)	2	(4)
Vagina had a change in odor or scent	7	(15)	9	(19)
How much did that bother you?—Not at all	1	(2)	0	(0)
A little/somewhat	5	(10)	9	(19)
Very much	1	(2)	0	(0)
How worried are you about the ring being dirty or unhygienic?
Not at all	36	(75)	27	(56)
A little/somewhat	11	(23)	21	(44)
Very much	1	(2)	0	(0)
How worried are you about the ring causing infection, infertility, or other long-term health problems?
Not at all	27	(56)	28	(58)
A little/somewhat	20	(42)	19	(40)
Very much	1	(2)	1	(2)
How much did it bother you to wear the ring during menses?
Median (IQR)	1	(1–2)	1	(1–3)
1 = Not at all	20	(42)	18	(38)
2 to 5	5	(10)	10	(21)
6 to 10 = Very much	4	(8)	2	(4)
NA, did not have menses while wearing ring in past 4 weeks	19	(40)	18	(38)
How often did you feel the ring inside you when you had sex?
Don’t know	20	(42)	14	(29)
Never	19	(40)	18	(38)
Some/most/all of the time	9	(19)	16	(33)
How much did it bother you?—Not at all	5	(10)	6	(13)
A little/somewhat	2	(4)	9	(19)
Very much	2	(4)	1	(2)

Worries about side effects and hygiene

At enrollment, roughly half of participants were either a little (47%, n = 23) or somewhat (4%, n = 2) worried about the ring causing infection, infertility, or other long-term health problems. This decreased slightly to 44% at Day 28 (n = 21) and 42% (n = 20) at PUEV (relative risk [RR] of worry at PUEV compared to enrollment 0.8, 95% CI 0.6, 1.1; p = 0.19). Conversely, concerns about ring hygiene increased over the study period. At enrollment, one-quarter of participants (27%, n = 13) were worried about the ring being unhygienic. By PUEV, 44% had concerns regarding hygiene (RR 1.6, 95% CI: 1.0, 2.6; p = 0.04). Among the 21 women who were a little or somewhat worried about hygiene at Day 91/PUEV, 4 (19%) preferred to use a 1-month ring, 15 (71%) preferred a 3-month ring, and 2 (10%) had no preference. Hence, the concern about hygiene appears to not have been strong enough to deter preference away from using a 90-day ring, given most still preferred a 3-month ring. Roughly half (56%, n = 27) noticed a change in their vaginal environment. The most common change was increased wetness (48%, n = 23), although most were not bothered by the change (52%, n = 12). Eleven women reported being bothered by increased wetness and nine reported being bothered by a change in odor. The nine women who reported being a little or somewhat bothered by the vagina having a change in odor or scent were the same women who reported being a little/somewhat bothered by the vagina being wetter. A few participants noted increased discharge (n = 3).

In qualitative interviews, participants brought up concerns about the cleanliness of the ring, perceiving that the ring would gather bacteria or cause infections over time. However, worries were minor, and most participants did not actually experience these side effects. One participant (San Francisco, 19 years old) described persistent worries by stating:

“let’s say I have something like a, like discharge or bleeding, yeah, I kind of might attribute it to the ring, but in reality it might not be from the ring. So, yeah, it’s just something that, it’s like, affects my mentality if something’s going on with my health issues.”

Some participants attributed perceived risk of side effects to the ring being left inside them for an extended duration, while others raised the opposite concern where they felt taking the ring out and touching it too frequently might increase risk. Overall, these concerns were described as minor, tempered by the idea that their bodies or vaginas would “let them know” if something was really wrong by causing a side effect such as a yeast infection. The concerns of hygiene usually did not outweigh the benefits. As one participant (San Francisco, age 19) stated, having some concerns about cleanliness was “worth it” to have the convenience of an extended duration ring.

Wearing the ring during menses and sex

Most participants were not bothered by wearing the ring during menses (60%, n = 18/30 experiencing menses); 7% (n = 2) at PUEV were moderately to very bothered (rating 6–10). By PUEV, 33% (N = 16/49) of women said they felt the ring some, most, or all of the time during sex. Among those who felt it, 56% (n = 9/16) said that it bothered them a little/somewhat and 6% (1/16) said it bothered them very much.

In qualitative interviews, participants described worries that sex would be “disrupted” in some way by the ring: because it would slip out, be felt by partners, or influence partners’ satisfaction. Several who felt the ring during sex described it as something that they were “aware of” or continuously “noticed.” However, “noticeability” of the ring was not necessarily uncomfortable or painful. This is exemplified by one participant (Birmingham, age 43 years) who described “it wasn’t really a pain, I could almost just like feel like he was hitting it, it was just a little discomfort.” Of note, two participants thought the ring increased sexual pleasure but were not exactly sure why.

On the other hand, a few noted that the ring was painful or uncomfortable for either them or their sex partners. “Bumping” or “hitting” the ring during sex was frustrating and it embarrassed some participants when the ring was felt by their partners or fell out. Importantly, despite any burdens or frustrations from wearing the ring during sex, participants noted that the benefits of using the ring “outweigh” these drawbacks.

Ring preferences and interest in MPT

At PUEV, most participants indicated preference for a 90-day ring (79%, n = 38; compared to 1 month 10% or no preference 10%) and one that could be worn continuously (83%, n = 40; compared to no preference 13% or before sex 4%) as shown in Fig 2. Three-fourths of participants (77%; n = 37) indicated they would be more likely to use a vaginal ring if it also prevented pregnancy, 11 (23%) participants indicated they were equally likely to use an MPT ring, and no participants said they would be less likely to use an MPT ring. Many participants had a partner that preferred the ring over condoms (44%), 27% had no primary partner, 19% didn’t know their partner’s preferences, 8% had partners who preferred oral PrEP, and 2% had partners that preferred condoms. Trends suggested that those who had penile-vaginal sex (91%, 20/22 versus 65%, 17/26; p = 0.05), and who were using a long-acting contraceptive method at baseline (91%, 20/22 versus 65%, 17/26; p = 0.05) were more likely to be interested in an MPT ring. Age, study site, whether the participant had menses while using the ring and prior history with vaginal products were not associated with MPT interest. However, provided there were only 11 participants that were not more likely to use an MPT, it was challenging to draw conclusions about factors associated with increased likelihood of using an MPT.

Fig 2

Measured preferences surrounding a vaginal ring for HIV prevention at product use end visit (PUEV), N = 48.

In qualitative interviews, all 25 participants were supportive of an MPT ring and most thought it would be a more appealing product, described as a “win-win,” “super convenient,” and a “bonus.” Some noted that they do not feel at risk of HIV personally but would consider using an MPT ring as their birth control method with the “added benefit” of protecting themselves from HIV “just in case.” Another common sentiment was that an MPT may not be right for them, given their low risk of HIV and unintended pregnancy, but it would be great for others who might take birth control but forget to protect themselves from other STIs like HIV. Interestingly, that was also seen as a drawback of the MPT whereby users might think they were fully protected and fail to protect against other STIs. As stated by one participant (Pittsburgh, age 38) “my only concern on it is that people would think that they were in the clear and it’s like, no, there’s a lot more STDs than just HIV.”

Several other minor concerns were noted, such as the safety of multiple drugs interacting, efficacy when combining multiple drugs and the ability to choose a hormonal contraceptive that best suits them. Ultimately, nearly all participants were supportive of an MPT ring for HIV and contraception, with the caveat that it should be safe and efficacious, and that users should also be reminded to protect themselves from other STIs.

Discussion

Acceptability of an extended duration vaginal ring for HIV prevention in this sample of healthy, HIV uninfected US participants was generally high with participants perceiving the ring to be easy to use and comfortable. Some participants noted that they could feel the ring during sex and had concerns about hygiene that increased over time, although these concerns were generally outweighed by the benefits of the extended duration. Interest for an MPT ring was high. The only concerns that emerged about an MPT ring were that it should be safe, efficacious, and that users should be reminded to protect themselves from other STIs that are not prevented by the product. The tenofovir ring may be able to protect against HSV-2 [21], one of the most common viral STIs, which could perhaps increase further the appeal of the tenofovir ring.

General measures of acceptability were high for the extended duration tenofovir ring. This is similar to findings from trials of other formulations of the ring to prevent HIV including the one-month dapivirine vaginal ring [22], the 3 month dapivirine ring [23], and the vaginal ring containing dapivirine, maraviroc, or both [24]. In the MTN-036 trial comparing the 1-month versus the 3-month DPV ring, which nearly 40% of our sample also participated in, most users preferred the 3-month ring at the end of the study period [17]. Concerns about the extended duration ring were similar to those found in this study: worries about hygiene, potential risk of vaginal infections, and other side effects (e.g. excessive vaginal discharge, odor). In both studies, the benefits of the 3-month ring seemed to outweigh concerns, leading most participants to ultimately choose the 3-month ring in MTN-036. Our study adds to this research by providing more data on women’s experiences using a 3-month ring with a different formulation, appearance, and physical dimensions (Fig 1), but more research is needed to directly compare ring options and to allow for user choice from a variety of ring products.

Prior studies have shown that tenofovir gel can reduce incidence of HSV-2 [3, 4, 25] and earlier studies of the tenofovir ring suggested the ring could deliver enough drug to be protective against both HIV and HSV-2 [21]. Furthermore, the ring is also being evaluated with levonorgestrel for hormonal contraception, as an MPT product with multiple indications [21]. While the ring evaluated in this study may protect against both HIV and HSV-2, participants were asked about interest in an MPT ring for HIV and pregnancy prevention. Interest in an MPT product was high among all participants in this study with some minor caveats about safety, and prevention of other STIs.

Our study had several limitations. First, the sample size was small with only 49 participants. The small sample size limited the inferences about acceptability and MPT interest, particularly in relation to how preferences varied by participant characteristics. Given the small sample, we also combined placebo and active product arms based on similarities in overall acceptability between the arms. However, it is possible that some components of acceptability may have differed by arm. Second, data in our study are from a randomized trial of the ring, and there may be some social desirability bias in answers about ring preferences or acceptability whereby users may respond in a more favorable manner. Given that acceptability responses were self-reported based on experiences using the ring in the trial, we cannot determine how their choices may differ outside of this setting or how preferences were potentially influenced by social desirability or recall bias. Although, measures were captured using CASI to encourage honest feedback compared to one another. Additionally, the trial included women in the United States who were at low risk for HIV and may not reflect preferences of women at higher risk for HIV acquisition or in other countries. Future studies should be done with women at higher risk of HIV and in a variety of settings. All participants were required to be using an effective method of contraception prior to enrollment and a high percentage (33%) were using an IUD for contraception. The sample may therefore be less generalizable and may have been more likely to prefer an MPT product. Lastly, a large percentage of our sample also participated in MTN-036 and had some familiarity with using a ring in an HIV prevention study. Our sample could be biased towards liking the ring if those who may not have liked the ring in MTN-036 did not enroll in MTN-038. Sexual partners were also not interviewed and may have influenced the decision of the participants to use the ring, although participants were asked about their partner’s support.

Conclusions

The 3-month extended duration tenofovir ring was highly acceptable and acceptability increased with use, similar to findings from previous studies of vaginal rings for HIV prevention and other indications. Some participants did have worries about side effects, hygiene and wearing the ring during sex, but these concerns were mostly minor and were often outweighed by the benefits of a long-acting ring. Interest in an MPT product was high and more research is needed to allow for user choice from a variety of ring products.

In depth interview guide used in the MTN 038 study.

(PDF)

Click here for additional data file.

12 Nov 2021

The reviewers feel that stronger descriptions of the medical device used in the study can further strengthen the manuscript. And, the reviewers have also provided additional discussion points for the authors to consider.

Could you please revise the manuscript to carefully address the concerns raised?

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” The MTN-038 study was designed and implemented by the Microbicide Trials Network (MTN) funded by the National Institute of Allergy and Infectious Diseases through individual grants (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The study investigators are thankful to CONRAD, which provided the rings with funding (AID-OAA-A-14-00010 and AID-OAA-A-14-00011) from the US Agency from International Development (USAID) and PEPFAR. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other agencies. We thank the study participants as well as the MTN 038 Study team members who implemented the trials.”

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“The MTN-038 study was designed and implemented by the Microbicide Trials Network (MTN) funded by the National Institute of Allergy and Infectious Diseases through individual grants (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. The study investigators are thankful to CONRAD, which provided the rings with funding (AID-OAA-A-14-00010 and AID-OAA-A-14-00011) from the US Agency from International Development (USAID) and PEPFAR. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other agencies. We thank the study participants as well as the MTN 038 Study team members who implemented the trials.”

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The paper describes user acceptability of a 90-day tenofovir-releasing vaginal ring for HIV prevention, as part of a Phase I trial. Acceptability data for a 30-day use regimen have previously been reported for the same ring device. Overall, the findings are consistent with previous reports for both this specific ring device and other vaginal ring devices. User interest in a hypothetical multipurpose ring – offering protection against both HIV infection and prevention of unintended pregnancy – was also evaluated.

The scope of the study is somewhat limited. As the authors, acknowledge, user acceptability data has already been reported for the one-month tenofovir ring, and this study simply extends the acceptability assessment out to three months. Were the researchers expecting the ring acceptability data to be different between the two use regimes? What additional information have they gleaned from this study that was unavailable from the previous study?

The study is further limited by having being conducted only in US women, rather than women in countries/communities where HIV prevalence is higher (e.g. Africa). I assume that such women are the primary market for a HIV prevention ring. Presumably, acceptability data could look very different comparing US women with African women? What was the rationale for conducting the study in US women? The authors need to comment on these issues.

Certainly, there is a need to assess user interest and preferences around an MPT ring for the purpose of informing future development of such products. However, the assessment described in the manuscript was the weakest aspect of this study, with only very limited data collected. It appears that only a single question on the topic was asked – “Would you be more likely to use a ring for HIV prevention if it could also prevent pregnancy (a dual-purpose ring)?”. A much more comprehensive study would have been helpful. For example, when presenting a hypothetical MPT ring to women combining HIV prevention and contraceptive activity, were women presented with hormonal or non-hormonal contraceptive options? Would the offer or one or the other impact user interest and preferences? Did women’s experience and satisfaction (or lack thereof) with current contraceptive use impact their preferences around an MPT ring? It was also noted that 24 (50%) of the 49 women enrolled in the study had experience with other vaginal ring devices, mostly as part of the MTN-036 trial. Did the previous experiences of these women impact their assessment and acceptability of the tenofovir ring in this study? Were the dapivirine and tenofovir rings similar in appearance and characteristics? Were any of the women currently using the contraceptive ring product NuvaRing? This would be important to know, since it would likely impact ring acceptability. I also assume that none of the women in this study were using Estring or Femring, as these are estrogen replacement products pimply indicated for us in older menopausal women; see footnote to Table 2. Surprisingly, none of these issues are documented or commented upon in the manuscript.

Did the quantitative behavioural study conducted by computer-assisted self-interview also capture information on the incidence and causes of involuntary ring expulsions? In Line 98, the authors refer to ring ‘displacement’. Does this refer to slipping of the ring within the vagina, without actual expulsion from the vagina? Please clarify.

The data collected around measures of acceptability are, of course, self-reported data, which are known to suffer from poor reliability. Any comments? For example, how do women’s reported preferences for a 90-day ring stack up against their concerns about long-term hygiene? If hygiene was an issue for some women, did these same women report a preference for the one-month ring?

PLOS ONE supports colour figures. It would have been helpful to colour code the bars in Figure 1 for ease of rating and interpreting the figure.

Reviewer #2: I thought this was really well written and a good example of using quantitative and qualitative data together (though I have very little qualitative experience so maybe I'm mistaken there). Quantitative methods-wise, this seems solid and I only have a few suggestions below to clarity and tighten a few loose bolts. Best of luck on future endeavors.

1. (lines 79-80) I find it really tough to know what to recommend for sample size calculation reporting in secondary analyses and sub-studies. I can understanding shifting these sorts of details to either a protocol publication or the main paper since usually trials were not powered for secondary analyses. Though, there's no word count for PLOS ONE and, at least for me, I regard this as pretty important information. How soon do you think the main MTN038 publication will be out? If you feel like it won't be out before this gets accepted, then I would include the sample size calculations here. If not, I'd still recommend including that info, but I'm fine if you still don't want to.

2. (line 134-135) I was a little confused about this statement because it suggests that you used Poisson regression for a binary outcome. Is this to obtain relative risks like is shown in https://doi.org/10.1093/aje/kwh090? If so, great, just please include that or another reference which explains the approach. Otherwise, maybe some editing or changes to the model are needed.

3. (line 136) Also a GEE reference here would be good.

4. For the quantitative analyses, please indicate the software and version used for analyses.

5. Although your confidence intervals say 95%, it's probably still worth noting in the quantitative methods second that you are using the 5% level of significance.

Reviewer #3: HIV prevention and reliable contraception are both important issues. Combination into one multi-purpose product would be an advantage for many women.

This study on the acceptability of a 3-month vaginal ring for HIV prevention and on the interest of the participants in a multi-purpose ring reveals interesting results for future implementation. However, several questions must be answered before acceptance.

Abstract: correct ‘form’ into ‘from’.

Introduction: no comment.

Materials and Methods

For the unfamiliar readers a short description of the ring used in the study would be very welcome.

Concerns about ring hygiene increased over the study period (Results). Was it allowed to take out the ring to clean it? If yes, please indicate for how long and how to clean? If not, can the authors discuss the pros and cons of this item in the Discussion section?

Was it allowed to take out the ring during intercourse? If yes, please indicate for how long? If not, can the authors discuss the pros and cons of this item in the Discussion section?

Results

Can the authors provide the number/percentage of partial and complete expulsions or slipping of the ring?

Table 3: at day 91/PUEV, the number of women who were bothered by ‘vagina was wetter’ and ‘vagina had a change in odor or scent’, were 11 and 9, respectively. Were these the same women? Can the authors provide data of vaginal cultures of these women? If not, discuss this in the Discussion section.

At day 91/PUEV, the number of women who felt the ring during sex some/most/all of the time was 16 (33%). These data in table 3 are not in correspondence with the text ‘By PUEV, 69% of those who reported wearing the ring during sex said they felt the ring at least some of the time (n=24/35); five (14%) felt it most or all of the time. Among those who felt it, 42% (n=10) said that it bothered them only a little (n=8). Can the authors elucidate this?

Figure 1: Insert bar with data on ‘Three-fourths of participants (77%; n=37) indicated they would be more likely to use a vaginal ring if it also prevented pregnancy, 11 (23%) participants indicated they were equally likely to use an MPT ring, and no participants said they would be less likely to use an MPT ring.’

The data of partner’s preferred product as shown in Figure 1 must also be described in the text.

Discussion

See above-mentioned items.

An important limitation of the study is that sexual partners have not been interviewed on their judgement of the ring as they may greatly influence the decision of the participants to use it. This must be discussed.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

5 Jan 2022

Reviewer's Responses to Questions

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

RESPONSE: Thank you for this review and for your support of our analysis and interpretations.

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

RESPONSE: We had added additional detail to the manuscript regarding the statistical analysis. Please see responses to review comments below.

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

RESPONSE Data are available through the Microbicide Trials Network (MTN). We have also now included a copy of the qualitative interview guide.

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

RESPONSE: We have edited the manuscript again and addressed all comments below.

Review Comments to Author:

Reviewer #1:

1.1 “The scope of the study is somewhat limited. As the authors, acknowledge, user acceptability data has already been reported for the one-month tenofovir ring, and this study simply extends the acceptability assessment out to three months. Were the researchers expecting the ring acceptability data to be different between the two use regimes? What additional information have they gleaned from this study that was unavailable from the previous study?”

RESPONSE: While similar products are available, we believe is still important to understand end user experiences and perspectives as new products are being developed because these findings will inform access and messaging when the product become available. In this case, the parent MTN 038 study was a clinical trial to assess the safety and pharmacokinetics of the three-month ring. However, we also assessed acceptability and preferences to inform how women use this product and concerns that might arise. We found that there were concerns about hygiene, sex and menses likely because of the longer duration of use. We also include a reference to the MTN 036 study comparing the dapivirine vaginal ring for 3 versus 1 month which found that users preferred 3-month rings despite having more hesitations or skepticism for the longer duration than a month-long ring.

To add to this point, we have edited the discussion section at line 290 to read as follows. “Our study adds to this research by providing more data on women’s experiences using a 3-month ring with a different formulation, but more research is needed to directly compare ring options and to allow for user choice from a variety of ring products.”

1.2 “The study is further limited by having being conducted only in US women, rather than women in countries/communities where HIV prevalence is higher (e.g. Africa). I assume that such women are the primary market for a HIV prevention ring. Presumably, acceptability data could look very different comparing US women with African women? What was the rationale for conducting the study in US women? The authors need to comment on these issues.”

RESPONSE: We agree that this ring should be available for women in all countries including the US and Africa. This study was a preliminary investigation to determine safety, pharmacokinetics and acceptability of the ring but we agree that future studies should be done in other populations. We have added this limitation to the discussion section at lines 311. “Additionally, the trial included women in the United States who were at low risk for HIV and may not reflect preferences of women at higher risk for HIV acquisition or in other countries. Future studies should be done with women at higher risk of HIV and in a variety of settings.”

1.3. “Certainly, there is a need to assess user interest and preferences around an MPT ring for the purpose of informing future development of such products. However, the assessment described in the manuscript was the weakest aspect of this study, with only very limited data collected. It appears that only a single question on the topic was asked – “Would you be more likely to use a ring for HIV prevention if it could also prevent pregnancy (a dual-purpose ring)?”. A much more comprehensive study would have been helpful. For example, when presenting a hypothetical MPT ring to women combining HIV prevention and contraceptive activity, were women presented with hormonal or non-hormonal contraceptive options? Would the offer or one or the other impact user interest and preferences?“

RESPONSE: We agree that the assessment of MPT interest and preferences is limited and should be followed up with additional research on more specific aspects of an MPT like hormonal and non-hormonal contraception options. This study was primarily descriptive and additional data were not available for analysis in this study.

1.4. “Did women’s experience and satisfaction (or lack thereof) with current contraceptive use impact their preferences around an MPT ring? It was also noted that 24 (50%) of the 49 women enrolled in the study had experience with other vaginal ring devices, mostly as part of the MTN-036 trial. Did the previous experiences of these women impact their assessment and acceptability of the tenofovir ring in this study? Were the dapivirine and tenofovir rings similar in appearance and characteristics? Were any of the women currently using the contraceptive ring product NuvaRing? This would be important to know, since it would likely impact ring acceptability. I also assume that none of the women in this study were using Estring or Femring, as these are estrogen replacement products pimply indicated for us in older menopausal women; see footnote to Table 2. Surprisingly, none of these issues are documented or commented upon in the manuscript.”

RESPONSE: We did examine predictors of MPT preferences including age, study site, whether the participant had menses while using the ring, whether (or how much) she engaged in penile-vaginal intercourse while using the ring, as well as prior history with vaginal products and contraceptive use. In the results at line 248 we note that “Trends suggested that those who had penile-vaginal sex (91%, 20/22 versus 65%, 17/26; p=0.05), and who were using a long-acting contraceptive method at baseline (91%, 20/22 versus 65%, 17/26; p=0.05) were more likely to use an MPT ring.” We did not include full results in a table because of small samples sizes. However, in the results at line 251 we have now added “Age, study site, whether the participant had menses while using the ring and prior history with vaginal products were not associated with MPT interest. However, provided there were only 11 participants that were not more likely to use an MPT, it was challenging to draw conclusions about factors associated with increased likelihood of using an MPT” We did not measure whether participants were satisfied with their current contractive method.

No participants were currently using a ring, Nuvaring or Estring or Femring. The footnote in Table 2 relates to whether participants had ever used a vaginal ring in the past. We have updated the text in Table 2 to “Prior use of a vaginal ring3” to clarify that it is not current use. We have also updated in the footnote to include counts of each type of ring experience “such as NuvaRing, Estring, Femring (N=12) or prior participant in trial of vaginal ring (N=19).” At line 177, we note that “Half (n=24) had prior experience using a vaginal ring, mostly from prior participation in another vaginal ring trial (MTN-036, n=19).”

Prior vaginal ring use was defined as use of the NuvaRing, Estring, Femring or prior participant in trial of vaginal ring. All vaginal rings approved for use in the United States were included in the protocol definition of vaginal ring use along with prior use of investigational vaginal rings during participation in previous research studies. Use of Estring and Femring were unlikely in this premenopausal population but were included to capture even the small chance of prior use. At line 157 in the methods we have now added “Prior history of vaginal products was defined as use of the NuvaRing, Estring, Femring or prior participant in trial of vaginal ring. Use of Estring and Femring were unlikely in this premenopausal population but were included to capture even the small chance of prior use.”

The tenofovir and dapivirine rings are similar but do have some differences. The tenofovir ring is a reservoir ring and has a 5.5 mm outer cross-sectional diameter and 55 mm outer diameter. A polyether urethane tube is sealed and joined together to form the shape of a ring. The dapivirine ring is difference and is a silicone polymer matrix-type ring and has a cross-sectional diameter of 7.7 mm and outer diameter of 56 mm. Injection molding of silicone elastomers forms the ring shape. We have added more details about the tenofovir ring in the methods at line 77, included a figure 1 with a photo of the ring and a reference to a ring comparison tool used in the MTN 038 study (See response to reviewer 3.1).

1.5. “Did the quantitative behavioural study conducted by computer-assisted self-interview also capture information on the incidence and causes of involuntary ring expulsions? In Line 98, the authors refer to ring ‘displacement’. Does this refer to slipping of the ring within the vagina, without actual expulsion from the vagina? Please clarify.”

RESPONSE: Information was captured about the incidence of ring expulsions/displacement and reasons. However, this information will be reported in the primary paper from the study and is not included here. We have edited line 112 to remove mention of displacement/expulsions.

1.6. “The data collected around measures of acceptability are, of course, self-reported data, which are known to suffer from poor reliability. Any comments? For example, how do women’s reported preferences for a 90-day ring stack up against their concerns about long-term hygiene? If hygiene was an issue for some women, did these same women report a preference for the one-month ring?”

RESPONSE: We agree with the reviewer that self-reported data can suffer from poor reliability because of social desirability or selective recall. However, acceptability is a subjective opinion which cannot be inferred entirely by clinical or laboratory assessments. For example, it is possible that the ring could cause an adverse event but that a participant may still find the ring acceptability because other benefits outweigh the concern. There are also some factors of acceptability which cannot be measured except by self-report, like how the ring feels in-situ and during intercourse. Even when clinical assessments cannot detect an issue, the participant’s perception and experience will ultimately influence their continual use of a product. Therefore, it is still valuable to collect participants’ perspectives and opinions. To encourage honest feedback and minimize social desirability bias, we measured acceptability via CASI (computer-assisted self-interviewing).

We have added the following to the results section at line 196. “Among the 21 women who were a little or somewhat worried about hygiene at Day 91/PUEV, 4 (19%) preferred to use a 1-month ring, 15 (71%) preferred a 3-month ring, and 2 (10%) had no preference. Hence, the concern about hygiene appears to not have been strong enough to deter preference away from using a 90-day ring, given most still preferred a 3-month ring.” This was also reflected in the qualitative data, as one participant shared that even with some concerns about hygiene, it was “worth it” to have the convenience of a 3-month ring.

Given the design of the study, we only assessed experiences using the ring and preferences based on those experiences. We did not measure how these preferences compare to one another or choices that would be made in a real-world setting. The following sentence has been added to the limitations on line 308 “Given that acceptability responses were self-reported based on experiences using the ring in the trial, we cannot determine how their choices may differ outside of this setting or how preferences were potentially influenced by social desirability or recall bias. Although, measures were captured using CASI to encourage honest feedback.”

1.7. “PLOS ONE supports colour figures. It would have been helpful to colour code the bars in Figure 1 for ease of rating and interpreting the figure.”

RESPONSE: We have now color-coded the bars in figure 1 (now figure 2 due to the addition of a new figure).

Reviewer #2:

2.1. “(lines 79-80) I find it really tough to know what to recommend for sample size calculation reporting In secondary analyses and sub-studies. I can understanding shifting these sorts of details to either a protocol publication or the main paper since usually trials were not powered for secondary analyses. Though, there's no word count for PLOS ONE and, at least for me, I regard this as pretty important information. How soon do you think the main MTN038 publication will be out? If you feel like it won't be out before this gets accepted, then I would include the sample size calculations here. If not, I'd still recommend including that info, but I'm fine if you still don't want to.”

RESPONSE: Additional details on the sample size calculation has been added to the methods at line 85. “Sample size calculations were based upon the size of similar Phase 1 studies of vaginal microbicide products and focused on the primary endpoints of safety and pharmacokinetics of the ring. Assuming a standard deviation of 2.4 from the acceptability score in a prior study, we estimated the study would have 90% power to detect a difference in the acceptability score of 2.65 with 32 participants. Additional detail on sample size calculations will be available in the primary publication from the study evaluating safety and pharmacokinetics of the ring.”

2.2. “(line 134-135) I was a little confused about this statement because it suggests that you used Poisson regression for a binary outcome. Is this to obtain relative risks like is shown in https://doi.org/10.1093/aje/kwh090? If so, great, just please include that or another reference which explains the approach. Otherwise, maybe some editing or changes to the model are needed.”

RESPONSE: Thank you for providing this reference. We have added the suggested reference by Zou et al. in the methods at line 150 in the manuscript and clarified that this was done to obtain a relative risk.

2.3. “(line 136) Also a GEE reference here would be good.”

RESPONSE: We have added a reference for the use of GEE to account for repeated measures at line 152 in the methods section.

2.4. “For the quantitative analyses, please indicate the software and version used for analyses.”

RESPONSE: The following sentence was added to the methods section at line 160. “All analyses were done with Stata version 16 (16.1, StataCorp LLC, College Station, TX).”

2.5. “Although your confidence intervals say 95%, it's probably still worth noting in the quantitative methods second that you are using the 5% level of significance.”

RESPONSE: The following sentence was added to the methods at line 154. “We used an alpha of 0.05 to determine statistical significance.”

Reviewer #3:

3.1. ‘Abstract: correct ‘form’ into ‘from’.”

RESPONSE: Thank you for catching this typo. “Form” has been edited to “from” in the abstract.

3.2. “Materials and Methods. For the unfamiliar readers a short description of the ring used in the study would be very welcome.”

RESPONSE: The following sentence has been added to the materials and methods at line 77 “The 1.4 g TFV ring consists of a drug-loaded hydrophilic polyether urethane tube (white segment) that is sealed and joined together (transparent joint) to form the shape of a ring. This is a reservoir ring using a water-absorbable polyurethane as a rate controlling membrane which can deliver approximately 10 mg/day TFV for 90 days (Fig 1). The TFV IVR has a 0.7 mm wall thickness, 5.5 mm outer cross-sectional diameter and 55 mm outer diameter. The dapivirine ring is slightly different and is a silicone polymer matrix-type ring with a cross-sectional diameter of 7.7 mm and outer diameter of 56 mm. A comparison of rings is available on the MTN 038 website.[13]”

3.3. “Concerns about ring hygiene increased over the study period (Results). Was it allowed to take out the ring to clean it? If yes, please indicate for how long and how to clean? If not, can the authors discuss the pros and cons of this item in the Discussion section? Was it allowed to take out the ring during intercourse? If yes, please indicate for how long? If not, can the authors discuss the pros and cons of this item in the Discussion section?”

RESPONSE: This is a good point. The following sentence has been added to the methods at line 97 to clarify. “Participants in the trial were instructed not to remove the ring for 90 days after insertion including during menses, to clean it, or for intercourse.”

3.5. “Results: Can the authors provide the number/percentage of partial and complete expulsions or slipping of the ring?”

RESPONSE: This information will be included in the primary manuscript from the study and is not reported in this manuscript.

3.6. “Table 3: at day 91/PUEV, the number of women who were bothered by ‘vagina was wetter’ and ‘vagina had a change in odor or scent’, were 11 and 9, respectively. Were these the same women? Can the authors provide data of vaginal cultures of these women? If not, discuss this in the Discussion section.”

RESPONSE: Yes, the nine women who reported being a little or somewhat bothered by the vagina having a change in odor or scent also reported being a little/somewhat bothered by the vagina being wetter. The following sentences have been added at line 202. “Eleven women reported being bothered by increased wetness and nine reported being bothered by a change in odor. The nine women who reported being a little or somewhat bothered by the vagina having a change in odor or scent were the same women who reported being a little/somewhat bothered by the vagina being wetter.” We are unable to present data on vaginal cultures because these data were not available at the time of this analysis and will be available in future publications from the study.

3.7. “At day 91/PUEV, the number of women who felt the ring during sex some/most/all of the time was 16 (33%). These data in table 3 are not in correspondence with the text ‘By PUEV, 69% of those who reported wearing the ring during sex said they felt the ring at least some of the time (n=24/35); five (14%) felt it most or all of the time. Among those who felt it, 42% (n=10) said that it bothered them only a little (n=8). Can the authors elucidate this?”

RESPONSE: Thank you for catching this issue. The text has now been edited in the results at line 224 to read “By PUEV, 33% (N=16/49) of women said they felt the ring some, most, or all of the time during sex. Among those who felt it, 56% (n=9/16) said that it bothered them a little/somewhat and 6% (1/16) said it bothered them very much. “

3.8. “Figure 1: Insert bar with data on ‘Three-fourths of participants (77%; n=37) indicated they would be more likely to use a vaginal ring if it also prevented pregnancy, 11 (23%) participants indicated they were equally likely to use an MPT ring, and no participants said they would be less likely to use an MPT ring.’ The data of partner’s preferred product as shown in Figure 1 must also be described in the text.”

RESPONSE: The following sentence has been added to the results section at line 246 “Most participants had a partner that preferred the ring (44%), 27% had no primary partner, 19% didn’t know their partner’s preferences, 8% had partners who preferred PrEP, and 2% had partners that preferred condoms.”

3.9. “Discussion. An important limitation of the study is that sexual partners have not been interviewed on their judgement of the ring as they may greatly influence the decision of the participants to use it. This must be discussed.”

RESPONSE: The following sentence has been added to the limitations on line 319 “Sexual partners were also not interviewed and may have influenced the decision of the participants to use the ring, although participants were asked about their partner’s support.”

Submitted filename: MTN 038 behavioral paper Reviewer comments and responses.docx

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25 Jan 2022

Acceptability of an extended duration vaginal ring for HIV prevention and interest in a multi-purpose ring

PONE-D-21-20792R1

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Additional Editor Comments (optional):

Based on the authors' comprehensive responses to the referees' comments and the accompanying edits to the manuscript, I am happy to recommend acceptance of this manuscript for publication in PLOS ONE. In the interests of transparency, I participated as a reviewer for the initial evaluation of this manuscript.

7 Feb 2022

PONE-D-21-20792R1

Acceptability of an extended duration vaginal ring for HIV prevention and interest in a multi-purpose ring

Dear Dr. Stoner:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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