-->PONE-D-25-59538-->-->HIV Incidence Among Sexually Active Young Males and Females in Kisumu County, Western Kenya-->-->PLOS One

Dear Dr. Crowell,

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As part of this process, the journal staff requested a review of previously published RV393 data to ensure this manuscript was not a re-publication of data. I appreciate the specific methodology describing RV393's enrollment, the inclusion of Figure 1, and the disclosure statement regarding the partial presentation of this data at CROI 2025.

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This work was supported by a cooperative agreement (W81XWH-11-2-0174; W81XWH-18-2-0040) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense. This research was funded, in part, by the U.S. National Institute of Allergy and Infectious Diseases.

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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?

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: 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: 1. Is the manuscript technically sound, and do the data support the conclusions?

Yes, this manuscript was technically sound and supported the conclusions. Overall, well written and put together and I did not identify any large issues. A few comments/questions regarding this section, specifically for the Methods section

A) On Page 6 it is listed that exclusion criteria include “significant conditions (medial, psychological/psychiatric, or social) that would interfere with study conduct”. There are then N=24 in Figure 1 who “Did not meet other eligibility requirements”. Are these the same group of individuals? I would recommend clarifying Figure 1 to address this, potentially just with different labeling in the text box. Also, I would suggest that in the methods section that the authors try to clarify what that above statement actually means. Is Medial supposed to be “Medical”? Are there specific, objective Medical or Psychiatric conditions that the authors pre-identified that they thought would interfere with the study conduct or was each individual excluded based on best judgment by a single person or by a group of investigators? I think this part was little vague and could be written more clearly in order to best follow the methods section.

B) During the methods section and Figure 1, I was a little confused if the authors were following more of a Per-Protocol or Intention to Treat methodology for the Person-Time calculations as mentions in the statistics section on page 8 and 9 of the draft manuscript. As an example, Figure 1 lists three categories for individuals removed in follow up (decision to withdraw, death, lost to follow up). Were these individuals who were excluded included at all in the analysis if they completed questionnaires and HIV but withdrew, died, or were lost to follow up at the very end of the study (or over the COVID-19 pause mentioned in the paper)? It might be helpful to list just an additional sentence or two clarifying if any of these were used in analysis and if not, why was that decision made (could put later in the manuscript). I was also a little confused about what would happen to participants who initially did not have exclusion criteria but potentially gained exclusion criteria later in the study. As an example, if an individual was not pregnant at screening but after a time period became pregnant, how much of that was used in the analysis for Person-Time calculation? Once again, the method section was very strong and technically sound, but a few areas of clarity might help the manuscript read a little better.

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

Yes, this manuscript has appropriate and rigorous statistical analysis. I only had a few comments on the statistical analysis section

A) It is very clear that authors only gathered behavioral survey data every 6 months (or up to 10 days after the HIV diagnosis) but I did not totally understand why the authors chose every 6 months versus every 3 months with the HIV testing? Was this just a logistical issue because of the burden of the survey? There is nothing wrong with this, but some clarification or justification might be beneficial. I think this is also important because the authors mention “recall and social desirability bias” on page 18, and I feel like adding length between the surveys likely added to this bias. Also, if a subject does test positive for HIV and then submits a survey, there might be a higher likelihood of recall bias if the individual already knows they have been recently diagnosed with HIV.

B) On Page 9 of the manuscript, it states “Variables that were significant in the unadjusted bivariable model were included in a fully-adjusted multivariable model except for participant sex”. I would recommend clarifying that the multivariable model adjusts for all the possible categorical variables. I think this is what was done in the statistical analysis, but it was not explicitly clear and could cause some confusion. Another option might be to edit Table 3 so the “Adjusted Relative Risk” column is a little more clear in the title or add this to the subtext you have on Page 15.

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

Yes, I believe all the data is fully available. I had no issues with the section. As mentioned above, it might be beneficial for the authors to clarify a few things in Figure 1 and data analysis in order to improve clarity for any readers; however, I feel like all the findings and data were clearly available.

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

Yes, overall I felt like the manuscript is very well written, presented clearly, and that the authors did a great job with their discussion section. I had two comments regarding this section

A) On page 6 line 86 of the manuscript draft the authors include the word “medial” as an example of a significant condition for exclusion criteria. Is this word intended to be “medical”?

B) On page 9 line 150 of the manuscript the authors state that they used “Byers” method for incidence rate confidence interval calculations. Was this meant to be written as “Byar’s” method, which I believe is the recognized standard spelling? This “Byer’s” spelling is also used in Table 2 on page 13 of the draft manuscript.

Reviewer #2: Question 1: Yes

This is a well-designed prospective cohort study examining HIV incidence among adults with multiple sexual partners in a high-burden setting in Western Kenya. Overall, the study is technically sound and clearly presented. The data support the authors’ primary conclusions, which are presented with humility and are not overreaching.

The longitudinal design, frequent HIV testing using what look like pre-established algorithms, and standardized behavioral data collection are appropriate. Laboratory procedures appear rigorous, and outcome ascertainment is well explained. Ethical oversight is strong (both Kenyan and U.S. IRBs). I appreciated the explanation of informed consent procedures.

The inclusion of a masking group of participants living with HIV is explained (HIV-related stigma in the community). However, this aspect of the design raises important questions. Perhaps a brief statement clarifying that these participants were aware of their HIV status, received appropriate counseling and linkage to care, and were aware that they were being enrolled as controls would help reassure readers less familiar with this approach.

Question 2: Yes

The statistical analyses are appropriate for the study design. Incidence rates are calculated using standard person-time methods suitable for rare events, and the authors do a good job of explaining incorporation of pandemic considerations. Cox proportional hazards models are used appropriately, and violations of proportional hazards assumptions are clearly stated. I appreciated that the authors avoid overfitting and interpret adjusted analyses cautiously.

The low number of incident HIV infections is an important limitation and is acknowledged. That said, the observed incidence remains higher than national estimates cited in the Background. This raises the question of whether anticipated incidence informed enrollment targets. Power/sample size calculations are not presented, so inclusion of a brief statement describing enrollment rationale or incidence assumptions (if there were any) would help readers better contextualize the study’s power to detect associations (or even whether this was considered in the study design).

Several points of clarity could strengthen the manuscript. In the Introduction, the discussion of “assessing the feasibility of future HIV vaccine and therapeutic trials” is somewhat unclear and does not clearly flow into the Results or Discussion. This should either be more explicitly addressed later in the manuscript or removed from the abstract and introduction. My first read of the manuscript was in the “assessing the feasibility” mindset, and I do not think this was an obvious throughline. A smaller point: for those of us less familiar, the description of fisherfolk would benefit from a brief explanation of their unique characteristics, especially if they represent a large portion of the study population.

In the Methods and Results, clearer wording would improve readability. For example, line 40: the variable describing unwanted sexual events should explicitly include the term “forced.” It is used in the table, but should be used here as well. By not including the word “forced,” this variable casts a much wider net. You should be clear here what you are implying, which I think is rape, assault, or coercion. Consistent formatting of numbers throughout the Results (particularly lines 171-174) would also improve readability. Consideration could also be given to including literacy in baseline characteristics if these data were collected, though education is used and is probably getting at the same thing.

In the Discussion, several interpretations could be sharpened. Comparisons with other incidence studies (lines 220-224) would benefit from consistent use of rates per 1000 person-years. Paragraph 219-228 raises the question of whether there have been similar studies in which incidence was markedly higher, or if low incidence is a persistent limitation in these types of studies. In lines 230-233, it may also be worth noting that individuals who self-select into longitudinal studies and are able to commit to follow-up may be more likely to adopt safer sexual behaviors over time. Additionally, the statement in lines 238-239 is too strong for something not statistically significant. I recommend dropping “This trend is consistent with” (line 239) and starting the sentence with “Regional…”.

Question 3: No

The authors state that restrictions will apply. They do have appropriate statements for data availability and requests.

Question 4: Yes

Overall, this is a solid and carefully conducted study that adds useful incidence data from a high-burden setting. The results are well presented, and the discussion is humble and even-handed. The suggested revisions are largely clarifying in nature and would further strengthen the manuscript without altering its main conclusions.

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Reviewer #1: No

Reviewer #2: No

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HIV Incidence Among Sexually Active Young Males and Females in Kisumu County, Western Kenya

PONE-D-25-59538R1

Dear Dr. Crowell,

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Kind regards,

Darrell Eugene Singer, M.D., M.P.H.

Academic Editor

PLOS One

Additional Editor Comments (optional):

On behalf of PLOS ONE and the reviewers, I thank the authors for addressing all comments and questions with this polished revised manuscript.

Reviewers' comments: