Dear Dr. Yovera-Aldana,

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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?

Reviewer #1: No

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: No

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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: No

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

Reviewer #1: No

Reviewer #2: No

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Reviewer #1: This manuscript addresses a public health issue, namely the burden of drug resistance among patients with pulmonary tuberculosis and type 2 diabetes mellitus in Peru. However, while the study provides useful descriptive data, several conceptual, methodological, and interpretative weaknesses limit the strength of the conclusions and require careful consideration.

Introduction:

The introduction adequately places the study within the broader global and regional context of tuberculosis

Methods:

The study population is drawn from a single, highly specialized referral centre that manages complex TB cases, including drug-resistant TB and patients with comorbidities. While this is clearly stated, the implications of this selection are insufficiently addressed throughout the manuscript. For example, the very high prevalence of MDR-TB and prior TB treatment (>80%) strongly suggests that the study population is not representative of the broader TB-DM population.

Regarding the four main anti-TB drugs, the fourth is pyrazinamide, not streptomycin, please clarify.

Diabetes treatment regimen classification is different between Methods section and Results section, please clarify.

Results:

Line 360: The authors mention “360 patients diagnosed with both diabetes and tuberculosis” during the study period. However, this number of patients is not mentioned anywhere else in the manuscript, not even in Figure 1. Please clarify.

Since the data in the "Total sample (N=144)" column of Table 1 are not mentioned in the text nor used anywhere in the manuscript, please delete this column or clarify how this data is relevant.

In Table 2, authors used HRZE abbreviations for anti-TB drugs but did not define all of them in the Table footnote. Furthermore, the abbreviation Z refers to pyrazinamide, but according to the Methods section, susceptibility to this antibiotic was not evaluated. Please clarify.

The authors analyse two outcomes: “Any drug resistance” and “MDR-TB”. However, since the MDR-TB category is included within the category any drug resistance, these two outcomes should not be treated and discussed separately in the main text.

In Table 3, percentages appear to be calculated by row rather than by column. While this presentation is mathematically correct, it makes it difficult to visually assess differences in the distributions between drug resistant positive and negative groups. A column-wise presentation (showing for example the distribution of age groups within each MDR-TB category) would be more intuitive and better aligned with the interpretation of Pearson’s chi-square test.

Lines 218-224: The authors say the same thing twice, just in different ways. Moreover, the youngest age group is not 40-49 years. Please rephrase. Please clarify the choice of variables for multivariable analysis.

Discussion:

The limitation related to recruitment from a specialized referral centre should be considered throughout the entire Discussion, rather than as an isolated point. This setting inherently selects for complex and drug-resistant TB cases, introducing substantial referral bias that affects prevalence estimates, observed associations, and their interpretation. The authors must revisit the entire discussion, systematically taking into account that this bias risk leading to an overinterpretation of the results and an extrapolation of the conclusions beyond the studied population. Moreover, in several places, the Discussion moves toward mechanistic explanations (immunosenescence, cumulative exposure, metabolic alterations) without sufficiently emphasizing the exploratory and observational nature of the findings.

Lines 255-256: The sentence “This study documents a high frequency of bacterial resistance to first-line anti-tuberculosis drugs among patients with tuberculosis and type 2 diabetes mellitus (TB-DM) co-infection” implies a comparative interpretation that is not directly supported by the study design. In the absence of a TB-only control group, the study cannot determine whether resistance is higher in TB–DM patients than in TB patients without diabetes. Moreover, recruitment from a specialized referral centre managing complex and drug-resistant TB cases introduces substantial selection bias, limiting the generalizability of the reported resistance frequency. Please rephrase.

Lines 270-271: Author state that: “However, the populations, levels of care, and methodologies included in those studies could explain the differences with our research.” Please elaborate further on this key point for the analysis of the study in light of the literature.

Lines 278-279: The manuscript refers to individuals aged 45-64 years as “young adults.” This terminology is misleading, as this age range is generally classified as middle-aged rather than young adulthood in epidemiological and clinical literature. Please use more appropriate age descriptors.

Line 346: The wording “clarified resistance patterns” is misleading. Multivariable analysis in this study does not resolve underlying resistance patterns but rather identifies exploratory associations within a selected referral population. Please rephrase.

Lines 358-361: Please specify more clearly what elements this study provides specifically.

General comments:

There are several typographical and grammatical errors throughout the manuscript that disrupt readability (spelling errors, inconsistent punctuation, use of the full word instead of the abbreviation).

There are sometimes discrepancies between the values in the main text and the Tables. Please correct them.

Authors used different terms to qualify resistance to at least one first-line anti-TB drug (any drug resistance, resistance to any first-line drug, any first-line drug resistance; of resistance to some first-line drug, resistance to at least one pharmaceutical agent, …) or resistance to at least two anti-TB drugs excluding MDR (oligoresistance and polyresistance), which is confusing. Please choose a single wording and keep it consistent throughout the manuscript.

This manuscript presents interesting descriptive data on drug-resistant TB among patients with T2DM. However, greater critical distance in the interpretation of results, clearer acknowledgment of selection and analytical limitations, and improved internal coherence would substantially strengthen the manuscript. Emphasizing the exploratory nature of the associations and avoiding over-interpretation would better align the conclusions with the data presented.

Reviewer #2: After the revision of the manuscript titled: High Prevalence of Resistance to First-Line Drugs and Multidrug Resistance in

Patients with Tuberculosis and Type 2 Diabetes Mellitus at a Referral Hospital in Peru. Here, the authors aim to to estimate the prevalence of resistance to first-line antituberculosis drugs and identify factors associated with multidrug resistance (MDR) among patients with T2DM and pulmonary TB treated at a public hospital in Lima, Peru. Despite their effort for a statistical analysis there are some points to be improved:

- it is not clear whether there is a diference between the drug resistant TB ( all types) to the drug suceptible gropup.

- Also, author should expand on the rationale on how DM is related to MDR-TB. Both the Introduction and the Discussion, warrant this connecting point.

There is as well other correcions including:

Introduction

• Line 77. Sentence is referring to the incidence of two diseases, but not clear which one.

Methodology

• Line 90. What is the exact population covered by this hospital? this is an important demgraphic data. It seems that this hospital recruits specifically complex cases. If yes, please underline how this setting can however be presented as paradigmatic of the entire MDR-TB problem in Peru.

Analysis plan:

• Please re-write the analysis plan using one whole paragraph. Please make sure to compile all methods correctly.

• Line 155 . Please clarify which method did you use for determining sample adequacy.

Result section:

• Results tables should be at the end of the manuscript.

• The entire section require restructuration and re-writte into adequate paragraph. Its current form only shows spare sentences stating the results. However, there is no connection of ideas among them.

Discussion section

• Line 294 Mycobacterium tuberculosis should always be in italics.

• Lines 302-313 should be a whole entire paragraph.

• Lines 315-325 again should be re-rewirtten into a whole paragraph.

• Lines 327-335 same

• The Discussion section does not provide any putative discussion/explanation/Link between  DM and MDR-TB (why would DM favor MDR-TB rather than Susceptbible TB ?) except that the studied setting. Please insist on this setting-linked limitation.

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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: No

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High Prevalence of Resistance to First-Line Drugs and Multidrug Resistance in Patients with Tuberculosis and Type 2 Diabetes Mellitus at a Referral Hospital in Peru

PONE-D-25-59435R1

Dear Dr. Yovera-Aldana ,

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,

Frederick Quinn

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

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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: (No Response)

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

Reviewer #1: Yes

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Reviewer #1: The authors have generally addressed the main points raised during the first round of review, and the revisions improve the clarity and consistency of the manuscript. A few remaining typographical and minor formatting errors are still present, but these can be resolved during the editorial processing stage.

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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

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