Dear Dr. Tigabie,

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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We look forward to receiving your revised manuscript.

Kind regards,

Amir Nutman

Academic Editor

PLOS ONE

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Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition).

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6. As required by our policy on Data Availability, please ensure your manuscript or supplementary information includes the following:

A numbered table of all studies identified in the literature search, including those that were excluded from the analyses. 

For every excluded study, the table should list the reason(s) for exclusion. 

If any of the included studies are unpublished, include a link (URL) to the primary source or detailed information about how the content can be accessed.

A table of all data extracted from the primary research sources for the systematic review and/or meta-analysis. The table must include the following information for each study:

Name of data extractors and date of data extraction

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All data extracted from each study for the reported systematic review and/or meta-analysis that would be needed to replicate your analyses.

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Additional Editor Comments:

Dear Authors,

Thank you for submitting your manuscript, “Extended-spectrum β-lactamase-producing gram-negative bacilli among people living with human immunodeficiency virus across the globe: a systematic review and meta-analysis” to PLOS ONE. Based on the reviewers’ comments, I invite you to submit a revised version.

Please address all reviewer points in a point-by-point response and highlight changes in the manuscript. This decision does not guarantee acceptance, but I believe the work has potential pending revision.

I look forward to your resubmission.

Best regards,

Amir

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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?

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

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: The authors conducted a systematic review and meta-analysis on the prevalence of ESBL in Gram negative bacteria among people with HIV. While the methods used for the analysis are appropriate, I have several concerns with regards to how the data are interpreted and reported.

Firstly, the main results on the prevalence of ESBL should be reported according to bacterial species and type (colonisation vs. infection). It is known that there are differences in ESBL prevalence between common Gram negatives such as E. coli and K. pneumoniae and pooling results across organisms is less meaningful. Further the authors should present as a main analysis (instead of a subgroup) the prevalence of ESBL in colonisation and infection samples.

Secondly the authors should note that for A. baumanii and P. aeruginosa, there are other mechanisms that play a more important role in beta-lactam resistance than ESBL-production. For this reason, the authors should restrict the focus of the manuscript on Enterobacterales and exclude A baumanii and P. aeruginosa.

Lastly, the authors should revise the manuscript to improve clarity and avoid repetitions. More specific comments are added below.

Lines 62-69: use concordant referencing. Currently you are reporting on data from various sources and the figures are somewhat conflicting. The O’Neill report which is almost 10 years old may have overestimated the number of deaths due to AMR. The paragraph would be easier to read if only one set of figures per point made would be used. Also in line 66 the sentence moves from economic losses in the US to global economic losses which is confusing.

Line 72: “Furthermore, the surge of infections that cause immune suppression, such as human immunodeficiency virus “ consider rephrasing as the infection you are referring to is HIV and there is no surge of multiple infections associated with immunosuppression. (unless you mean conditions associated with immunosuppression e.g. long-term steroids etc.

Lines 82-84: introduce the epidemiology of HIV before introducing how it relates to resistance development

Line 90: “Among bacterial pathogens, gram negative bacilli are the most dangerous …” while it is true that gram-negative organisms pose more problems because of their resistance to antibiotics, they are not necessarily more dangerous (unless a reference is provided to support that statement e.g. that bacterial infections due to gram-negatives cause more deaths).

Line 95: “cephalosporins, and aztreonam, which are easily available” remove aztreonam from the listing as it is not easily available and commonly used

Line 97: “Enterobacteriaceae, Pseudomonas aeruginosa (P. aeruginosa), and Acinetobacter baumannii (A. baumannii) are the predominant gram-negative bacilli that produce ESBL enzymes “ please revise the sentence – the main mechanisms associated with resistance for P aeruginosa and A. baumanii are not ESBL-production.

Lines 105-107 – “the number of ESBL-producing gram-negative bacilli among HIV-positive individuals varies from 2.3% to 65.6%” – these are proportions not numbers

Lines 109-110: “On the one hand, various studies in the past reported higher ESBLs among HIV-positive individuals [20-29]. On the other hand, some studies reported that ESBL producers were more common among HIV-negative patients than among HIV-positive individuals [30-32].” – please consolidate these sentences to avoid repetitions

Line 139: please clarify in the methods whether the review included studies reporting exclusively on people living with HIV or it also included studies with mixed populations which reported on AMR prevalence by HIV status

Line 157: “The three reviewers listed above, MT, KT, and AB, were independently assessed to assess the quality of the included studies.” Please revise to avoid repetition

Figure 1: conventionally in the PRISMA diagram, the studies are reported separately as to how many were excluded in the title and abstract screening (reason for exclusion not necessary) and how many were excluded in the full text phase (with reason for exclusion).

Line 214 and above: be specific in the methods on how the prevalence was calculated for case-control studies (depending on the study design, might only be possible to calculate prevalence in the cases)

Table 1: please check and/or comment on including studies on infection which reported on stool samples. In this setting ESBL-producing organisms are also likely to represent colonisation (e.g. the study by Falodun reference #23 et al is clearly reporting on colonisation). Also check as there is an error with reference #22 which is a different study by Falodun et al. (not Israel)

Line 231: please note that it is not appropriate to pool prevalence across very different bacterial species and sample types. At least the pooling should be done separately for colonisation and infection and ideally separate for the main Enterobacterales species. This should not be treated as a subgroup analysis but rather the main analysis. I would suggest that you omit Pseudomonas and Acinetobacter completely from the analysis and manuscript as these organisms have additional mechanisms causing beta-lactam resistance, other than ESBL.

Table 2: “Rate of ESBL…” heading – please rename as this is not a rate (prevalence).

Table 2: Comment separately in the manuscript text on the prevalence of ESBL in Salmonella – 20% is quite high and concerning for clinical practice.

Table 3: can be omitted

Figure 3 should be redrawn as it is difficult to read with a black background. Also the numbers on the x-axis are overlapping. The figure can be included in the supplement.

Line 279: the subgroup analysis on method used can be omitted (or included in the supplement). For the other subgroup analyses please see my comment above. The authors could also add a subgroup analysis by organism and type (colonisation vs. infection) for community-acquired and hospital associated infections

Table 5 and Supplement: the genes should be reported according to the bacterial species in which they were identified (consider reporting for E. coli and K. pneumoniae only). Please also specify which SHV/CTX-M/TEM/OXA genes were reported as not all of them are ESBL

Line 322: please rephrase. The organisms are not multidrug resistant because they are ESBL-producers (there is a somewhat old definition of MDR and being ESBL does not suffice).

Line 339: please revise as E. coli is a common cause of community-acquired infections

Line 377: the higher prevalence may be explained by the methods used to report on colonisation (denominators, method of detection – culture media).

Lines 401-410: paragraph has repetitive sentences please revise

Reviewer #2: This systematic review and meta-analysis provide valuable insights into ESBL prevalence among HIV-positive individuals. While the study is methodologically strong, improvements in data selection, bias reduction, and clinical interpretation could enhance its impact. Future research should focus on treatment outcomes, stewardship interventions, and emerging resistance mechanisms to inform better infection control policies in HIV care settings.The study adheres to PRISMA guidelines, ensuring methodological transparency. It addresses a critical intersection of HIV and antimicrobial resistance (AMR), a growing concern for global health.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: Yes:  Rahul Garg

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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.

Dear Dr. Tigabie,

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.

Please submit your revised manuscript by Jun 11 2025 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.

• 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 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Amir Nutman

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Thank you for your submission.

After reviewing the revised manuscript, I find it acceptable pending minor revisions:

1. The manuscript would benefit from language editing by a fluent English speaker to improve overall readability.

2. When reporting prevalence percentages, please also indicate the numerator and denominator (e.g., x/y, z%) to enhance clarity.

3. In Supplementary Table 2, only one author is listed as performing data extraction, which does not align with the description in lines 212–213 of the main text. Please correct this inconsistency.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

Reviewer #1: All my previous comments have been addressed.

However I am slightly confused by the different prevalences reported - perhaps because of numerators and denominators "The predominant ESBL producers were K. pneumoniae, with a pooled prevalence of 40.84% (95% CI: 26.87–54.81%), followed closely by E. coli at 40.14% (95% CI: 27.83–52.45%). In the subgroup analysis, the highest magnitude of ESBL producing pathogens was observed in Asia (28.5534.97%), followed by Africa (19.1220.75%). Additionally, the highest pooled prevalence of ESBL-producing pathogens among HIV-positive individuals was reported to be colonization 23.78% (95% CI: 15.36–32.19, I² = 96.78%, p <0.001), followed by infection 15.77% (95% CI: 10.06–21.49, I² = 97.45%, p < 0.001). "

The pooled prevalence of ESBL E coli is reported above at 40% and below at 15-23%. Also for the subgroup analyses by country there are prevalences around 20% by continent while overall it is 40%.

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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: 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

<p>Extended-spectrum β-lactamase-producing Enterobacterales among people living with human immunodeficiency virus across the globe: a systematic review and meta-analysis

PONE-D-24-40800R2

Dear Dr. Tigabie,

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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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Amir Nutman

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

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

Reviewer #1: Yes

**********

Reviewer #1: The authors have provided responses to my comments (from the previous round of review) and I have no further comments.

**********

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: No

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