PONE-D-24-20929Predictors of maternal HIV acquisition during pregnancy and lactation in sub-Saharan Africa:  a systematic review and narrative synthesisPLOS ONE

Dear Dr. Graybill,

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Academic Editor

PLOS ONE

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Additional Editor Comments:

Dear Authors,

Thank you for submitting your manuscript titled “Predictors of maternal HIV acquisition during pregnancy and lactation in sub-Saharan Africa: a systematic review and narrative synthesis” for review. . Below are my comments that you might address or clarify, which I hope will assist you in enhancing the manuscript.

1. Methodological Concerns

1.1 Heterogeneity in Predictor Definitions

There is considerable variability in how key predictors (e.g., STIs, condom use, multiple partners) were defined across the included studies. The manuscript acknowledges this variability but does not address how it impacts the overall interpretation of results.

Consider providing a more robust discussion on how the varying definitions of predictors could have influenced your findings. A sensitivity analysis or stratified synthesis, where you group studies based on the homogeneity of predictor definitions, would add rigor to your approach.

1.2 Exclusion of Predictors Assessed in Fewer Than Four Studies

Excluding predictors evaluated in fewer than four studies may result in the omission of important but less-studied risk factors.

Recommendation: Provide a brief discussion of the predictors that were excluded and highlight any that may be emerging as important in other contexts or regions. If possible, explore these predictors narratively, even if formal synthesis was not feasible.

1.3 Limited Consideration of Confounders

The manuscript lacks adequate discussion of how confounding variables (e.g., socioeconomic status, healthcare access) were addressed in the included studies.

Add a section that categorizes how well the included studies adjusted for key confounders. Where confounding was not properly addressed, note how this limitation could affect the interpretation of the findings. This is particularly important for predictors like age and multiple partners, where social and healthcare access factors might play a significant role.

2. Presentation of Data and Interpretation of Results

2.1 Confidence Intervals and Precision

Many associations are reported without sufficient emphasis on the confidence limit ratios (CLRs) or the wide confidence intervals seen in certain predictors, which could indicate high imprecision.

Place greater emphasis on the interpretation of these confidence intervals and discuss how imprecision affects the reliability of the findings. If the CLRs indicate high variability, it would be important to highlight this as a limitation in your results.

2.2 Interpretation of Unexpected Findings (e.g., Condom Use)

The finding that consistent condom use is associated with a higher risk of HIV acquisition is counterintuitive and requires a deeper exploration of potential biases or alternative explanations.

Acknowledge the potential for reporting biases or misclassification of condom use. It is also important to discuss whether consistent condom use is related to other confounding variables, such as higher sexual activity, which may explain the increased risk observed.

2.3 Underrepresentation of Regional Differences

The exclusion of studies from Western Africa and non-English studies raises concerns about generalizability.

Include a more detailed discussion of how this exclusion impacts the conclusions, particularly given the diverse healthcare and cultural contexts in sub-Saharan Africa

3. Discussion and Implications for Policy and Practice

3.1 Lack of Practical Implications for Healthcare Providers

The manuscript focuses on identifying predictors but lacks specific recommendations for how these findings can be used in clinical practice or policy development.

Strengthen the discussion by providing concrete suggestions for how healthcare providers in sub-Saharan Africa can use these predictors in clinical decision-making. For instance, how can HIV risk screening be adapted based on the predictors identified in your review? What are the implications for PrEP implementation or antenatal care protocols?

3.2 Policy Recommendations

The current policy implications are underdeveloped and lack specificity.

Provide a more detailed exploration of how your findings align with or challenge current WHO recommendations. You could also offer suggestions for regional or national health policies that could be adapted to better address the identified predictors of HIV acquisition.

4. Clarity and Organization

4.1 Consistency in Data Presentation

Data presentation is sometimes inconsistent, particularly in terms of reporting confidence intervals and discussing effect sizes.

Ensure that all data, especially confidence intervals, are consistently reported. This will help readers more easily assess the strength and precision of your findings.

5.1 Expansion of Limitations and Future Research Directions

The limitations section is currently underdeveloped, particularly around the methodological choices made (e.g., vote counting, reliance on self-reported data).

Expand the limitations section to address the methodological constraints, including the exclusion of certain predictors and the impact of self-reported data. Additionally, provide more specific future research directions, such as focusing on under-researched predictors or conducting more region-specific analyses.

6. Engagement with Current Literature

6.1 Integration with Recent Studies and Trends

The manuscript does not sufficiently engage with recent advancements in HIV prevention, such as the growing use of PrEP or novel behavioral interventions.

Incorporate a discussion on how PrEP, telehealth, and other modern interventions could interact with the predictors you identified. This would make the paper more relevant to current clinical and policy debates.

Conclusion:

I look forward to reviewing a revised version.

Best regards,

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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

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

Reviewer #1: N/A

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: 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: This is a well-written systematic meta-review of literature from SSA regarding risk factors for HIV acquisition among pregnant and lactating women. It includes 3+ decades of literature and identifies a common set of risk factors associated with HIV acquisition during pregnancy and lactation. The authors undergo a robust critique of the included manuscripts and draw measured conclusions about the common factors identified.

Background:

Would include brief discussion of why women are at particular risk of HIV during pregnancy and lactation. (social/family factors, biology/immunologic factors) Mofesen 2018 might be helpful here.

Would also include a brief context of the epidemiology of HIV acquisition among PLW in SSA.

Methods:

Initially your wide date range for inclusion struck me as a limitation—how relevant could studies of HIV acquisition risk in the late 80’s be for this analysis?—but ultimately the data convinced me in that the same themes emerged throughout the 30+ years you included. I think you would draw the same conclusions from a more narrow, homogeneous time period though I agree that the consistency of the themes over that period actually end up adding validity to your conclusion.

Results:

The tables are clear and helpful.

Discussion:

458-60: It was unclear to me what you meant by this sentence.

466: Can you say more here about current performance of the risk assessment tools you mention—either specifically more about the Kenya tool or provide an additional example? The discussion of risk factors is nuanced but I am left without a clear sense of how these findings could augment current practice.

Reviewer #2: The authors did an excellent job of synthesizing the diverse and broad range of published individual risk factors for acquiring HIV during pregnancy and lactation, using the standard PRISMA guidelines for systematic review. The authors struck a good balance of providing the diversity of various risk factor definitions and risk periods and distilling these definitions to meaningful categories. In discrete datasets, the analytic approach is generally to identify risk factors significantly associated with incident HIV and then to perform a multiple regression analysis to identify the subset of factors that remain independently associated with HIV incidence, since risk factors can confound the individual associations. The authors acknowledge this possibility in the Discussion (lines 455-457) by noting that the association between condom use and HIV infection could be confounded by other risk factors such as multiple sexual partners or having a partner living with untreated HIV. The diversity of type and definition of predictors precluded meta-analysis; however, I think that the discussion could have benefitted from a more robust discussion on the interplay between different risk factors and how to deal analytically with confounders in a risk scoring system- it's not just an issue of understanding that association does not mean causation (lines 491-2). The authors mention that some risk factors are self-reported. People might not be completely transparent about socially stigmatizing risks, and as noted, risks can be transitory. There has been a recent shift in prevention to deemphasize risk screening tools and instead provide prevention methods based on self-perceived risk, which the authors note was consistently associated with maternal HIV acquisition. Table 2 shows a moderate to high risk of bias in the publications. Given these limitations, in the discussion, I encourage you to reflect on the advantages/ disadvantages of a universal vs risk-based approach as trialed in the PrIMA study by Kinuthia, J., et al. (2023). "Risk-based versus universal PrEP delivery during pregnancy: a cluster randomized trial in Western Kenya from 2018 to 2019." J Int AIDS Soc 26(2): e26061. I realize this universal offer approach undermines the premise of this systematic review; however, it is a pragmatic alternative approach that could be acknowledged in the limitations. Another angle on the differences between studies is who was asking the risk questions and where. Participants might be more willing to be accurate (or honest) in certain circumstances (private location) and to certain interviewers. Specific minor points are that the legend in Figure 2 (page 50-54) are small and difficult to read, which makes it difficult to grasp what variable the forest plots are trying to show. You had a clear rationale for selecting risk factors that were assessed in at least 4 publications. That's an okay rationale - you had to limit in some way: however, I might have weighted the large studies (Dihn, Humphrey, Mussa, Woldesenbet) with many seroconversions that assessed risk factors (such as age difference) that didn't quite make the 4 study mark. (again, a minor issue)

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Reviewer #1: No

Reviewer #2: Yes: Wm. Perry Killam

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Predictors of maternal HIV acquisition during pregnancy and lactation in sub-Saharan Africa:  a systematic review and narrative synthesis

PONE-D-24-20929R1

Dear Dr. Graybill,

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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Kind regards,

Garumma Tolu Feyissa, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: All comments have been addressed

Reviewer #2: All comments have been addressed

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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

Reviewer #2: Yes

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

Reviewer #1: N/A

Reviewer #2: Yes

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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: Yes

Reviewer #2: Yes

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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: Yes

Reviewer #2: Yes

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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: Appreciate your responses to my particular comments, as well as the comments by the other reviewer. This is a comprehensive meta-analysis of literature, though agree with the other review that an update will be imminently needed in light of some of the recent advances in PrEP provision among PBFW in sub-Saharan Africa.

Reviewer #2: Thank you for responding to our comments. I think this is now a stronger paper, and I recommend that PLOS One accept it.

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Reviewer #1: No

Reviewer #2: Yes: Wm. Perry Killam

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