PONE-D-21-20792Acceptability of an extended duration vaginal ring for HIV prevention and interest in a multi-purpose ringPLOS ONE

Dear Dr. Stoner,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The manuscript has been evaluated by three reviewers, and their comments are available below.

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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2. Please include a copy of the interview guide used in the study, in both the original language and English, as Supporting Information, or include a citation if it has been published previously.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

” 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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“Dr. Chen receives research grants from Medicines360 and Sebela, which are all managed by Magee-Womens Research Institute. All other authors declare no conflict of interest.”

We note that one or more of the authors are employed by a commercial company: Medicines360 and Sebela

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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

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

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

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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

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

PONE-D-21-20792R1

Dear Dr. Stoner,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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R. Karl Malcolm, PhD

Guest Editor

PLOS ONE

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.