PONE-D-20-27294

Low use of condom and high STI incidence among men who have sex with men and in transgender women in PrEP programs

PLOS ONE

Dear Dr. Ayerdi Aguirrebengoa,

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.

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Please note that both reviewers raised important questions that should be addressed in a revised version of the manuscript including concerns about overinterpreting results with n=2 TGW (and inclusion of TGW in the title), patterns of PrEP use (daily/on demand), and some of the statistical interpretations. 

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Please submit your revised manuscript by Dec 10 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

J. Gerardo García-Lerma, Ph.D.

Academic Editor

PLOS ONE

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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: No

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: Yes

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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: No

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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: This manuscript describes clinical and behavioral characteristics of a cohort of PrEP users in Madrid, Spain. The study provides valuable data on STI incidence, sexual risk and substance use behaviors in this group, and this report is especially timely given the recent expansion of public medical coverage in Spain to include PrEP. The regular collection of STI screening data that is clinically verified is an especially valuable contribution. However, there are many methodological details not presented that make interpreting this paper challenging.

Major issues:

1) The title and abstract describe the cohort as “men who have sex with men and transgender women” but the cohort in fact only includes 2 TGW. While there is a clear need for data on STI incidence and behavioral risk factors among TGS PrEP users, I don’t believe it’s appropriate to group them with the rest of this this cohort with the ability to do more detailed sub-group analyses to determine whether the findings are consistent for this population. I believe it would be more appropriate exclude these two participants from this analysis and define the cohort as exclusively cisgender men who have sex with men.

2) The Methods section is currently lacking in sufficient detail to interpret the results and discussion presented. Most critically, I question whether this can be accurately described as a study of risk compensation among PrEP users because there is no control group of non-PrEP users (as mentioned in the limitations), it is not clear whether all participants were already on PrEP at the commencement of the study, and what time frame was being recalled when asked about condom use and substance use before the study. Because high sexual risk and STI infection are indications for PrEP prescription in the first place, this could simply be reporting STI incidence in a cohort of high-risk MSM. Still could be valuable to report, but not in the risk compensation framing.

3) Some details that should be added to the Methods to help interpret this study are as follows:

a. What was the eligibility criteria for participants?

b. Where all participants on PrEP at baseline?

c. What was assessed at baseline and at follow-up surveys? How many follow-up surveys were conducted? Unclear whether it was one at the end of the study or at each of the 3 month screening visits.

d. Adherence to PrEP was assessed as >90% of what? Doses? Over how many days?

e. Condom use before/after PrEP: Time frame for each? What does % refer to? Partners, encounters?

f. Number of partners before/after PrEP: Time frame for each?

g. Time frame/frequency for substance use behaviors? Also, since substance use as defined was near-universal (94.5%), perhaps the authors could consider a different definition of this variable that would have more variability. I assume alcohol use is highly prevalent in this population (as it is in the general population) and not all use is necessarily problematic. The same can be said for drugs like cannabis.

Minor issues:

1) The third paragraph of the Results section could use some copy-editing. Sentence construction like “…the 85.4% (94) use condom usually” is not grammatically correct. Furthermore, the number in parenthesis can be easily confused as a reference number. Would recommend revising to “…85.4% (n=94) of participants used condoms usually” throughout this paragraph.

2) Some improper hyphenation of terms: “recreational-drug use”,

3) Would recommend revision of a few terms:

a. “Qualitative variables” should be “Dichotomous variables”

b. “Quantitative variables” should be “Continuous variables”

c. “Toxic habits” should be “substance use”

d. “univariate analysis” should be “bivariate analysis” (because the model was testing associations between two variables)

4) Some typos identified:

a. “analized” should be “analyzed”

b. “inercourse" should be “intercourse”

c. A couple of instances of “more tan”, which should be “more than”

5) Reference 15 appears to be missing a title.

Reviewer #2: This paper presents an analysis of clinic patients using PrEP from 2017 thru 2019 that looked at the association of STI incidence and condom use, number of sex partners, chemsex. A significant decrease in condom use for anal intercourse was observed after PrEP initiation, but no significant change in number of partners was observed. There were also no changes in recreational drug use observed. This research is important and current as the research on PrEP use and behavioral disinhibition, or risk compensation, is still new and findings have future implications for PrEP implementation.

The manuscript needs to be reviewed for grammar and syntax, preferably by a native English speaker to improve clarity of your prose. Below are my comments and questions.

Minor comments and questions:

-You establish that alcohol and other recreational drugs use are common and 90% reported no increase in the study period. With that said, a lot of data are presented regarding drug use and condomless sex, however it does not seem related to the research question regarding PrEP use. For conciseness, is it possible to omit these findings since they do not relate to, or contribute to answering, the research question?

-The previous comment applies to findings on erection-enhancing substances and using dating apps.

-It would be nice to have a table or figure representing the data on behavioral changes regarding condom use and number of sexual partners before and after PreP was initiated

-Variables are not operationalized the same way. For example, "unprotected sex…" and "condomless sex…" are referring to the same thing. Variable names should be consistent throughout the text and with tables and figures.

Abstract:

-Was statistical significance for the analysis conducted set to 0.10? Methods section indicates only 0.05 threshold. Unless the 0.10 threshold was used for model building (regression analysis), this value should be consistent for significance testing.

Introduction:

-Was the any previous efforts to alleviate risk compensation behaviors in the specialized referral clinic this study took place?

Methods:

-Statistical analysis - count data is quantitative data, not qualitative, is it not?

Results:

- "We found that 15.6% of patients reported missing a dose while under the effects of alcohol or other recreational drugs."

I suggest moving this to the discussion section; this finding seems extraneous and does not contribute to the research question, although it is interesting.

-"Alcohol and other recreational drugs were consumed by 94.5% PrEP users, of whom 89.9% reported no increased consumption of these substances"

Was alcohol and recreational drug use assessed at the follow-up points to examine change in drug use during PrEP use or was change in drug use assessed only at the end?

-"Condomless sex under the influence of recreational drugs" and "Sexualized drug" are referring to the same thing, however the former is only used in the table. I suggest adding this explanation in the text or making it consistent.

-"…changes were compared to the first semester." Because STI incidence/IRR's are being calculated, were the assessment of STI's at each follow-up point ensured to be new infections if STI was reported at baseline or previous follow-up points.

-"Condom use for anal intercourse before start of PrEP" was not significant in the univariate analysis; the confidence interval includes 1 indicating the null hypothesis of no association is not rejected. Please change results and relevant text accordingly.

-Infrequent condom use does not need to be reported as significant at <0.10 if significance threshold is <0.05 for all other analyses.

Discussion:

- "In spite of evidence indicating that engaging in chemsex increases the risk of STI transmission, in our study we observed no significant difference in adherence, a finding also reported in the study by O’Halloran et al. (18)." What is the no difference in adherence referring to? PrEP? And how is the first part (chemsex) of this statement related to this study finding?

-Are there any current or planned future strategize for the specialized referral clinic this study took place?

Tables and figures:

-Was Age and Condomless sex under the influence by drug type analyzed differently than the other variables? A reference category in the univariate analysis is not specified.

-How was the Age variable coded in the multivariate analysis? Based on the results and 0.978 point estimate patients over 30 years old were the reference group?

-Why was Condomless sex under the influence by drug type and Chemsex not included in the multivariate analysis? Chemsex indicates a significant association (as well as some few drugs in the first variable) in the univariate analysis. The rationale for this is found in the results, but I suggest moving to methods section so that readers are aware of this decisions before reading the results/table. Or possibly, you could not present the data not being used in the final report.

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Reviewer #1: No

Reviewer #2: Yes: Jeffrey S Becasen

[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.]

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PONE-D-20-27294R1

Low use of condom and high STI incidence among men who have sex with men in PrEP programs

PLOS ONE

Dear Dr. Ayerdi Aguirrebengoa,

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.

==============================

Although much improved, one of the reviewers still has some minor comments that need to be addressed before we can consider it for publication. 

==============================

Please submit your revised manuscript by Feb 01 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

J. Gerardo García-Lerma, Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

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2. 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

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

Reviewer #1: Yes

**********

4. 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: No

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5. 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: No

**********

6. 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: Overall, I find this manuscript to be much improved following revisions. Aside from a few more minor comments, enumerated below, I find this manuscript to be publishable.

Minor comments:

1. Did any participants discontinue PrEP over the course of the follow-up? Or was the sample selected to include only those who stayed on PrEP for the duration of the study period? Either way, please include this information in the Methods section.

2. Table 3 mentions "any distant metastases" under "CT" but this was not included in the Methods section.

3. This manuscript would benefit for one more round of copy-editing for English grammar/style, especially in the Methods and Results sections. Some suggested revisions:

Methods:

- The sentence about eligibility criteria should read: "The eligibility criteria was taking PrEP, so all participants had sexual risk indications for this preventative measure as proposed by the guidelines [reference? More clarity on which guidelines needed here] and started taking PrEP at the first visit of the study."

- "sexualized drug use" instead of just "sexualized drugs"

Results:

- "the 85.4% (n=94) of participants" should just read "85.4% (n=94) of participants". There are a few other instances of this sentence structure in the same paragraph, which should be revised similarly.

- "...consumed by 94.5% of PrEP users" (missing the word of)

- some inconsistency with how % are reported, i.e. sometimes with (n=) and sometimes without. Please revise such that all are consistent and according to journal standards.

- "It is also determined the number of diagnosed STIs per individual." - I don't understand this sentence and it is not clear what result this is reporting.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Maria Zlotorzynska

[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.

Low use of condom and high STI incidence among men who have sex with men in PrEP programs

PONE-D-20-27294R2

Dear Dr. Ayerdi Aguirrebengoa,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

J. Gerardo García-Lerma, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: