Review Reports - Relationship Between Onychomycosis and HIV: A Systematic Review

Round 1

Reviewer 1 Report

This manuscript presents a systematic review investigating the association between onychomycosis and HIV infection, analyzing data from more than 1,200 patients worldwide. The findings indicate that individuals living with HIV have approximately a fourfold increased risk of developing onychomycosis compared to the general population, and the condition tends to be more severe or refractory to treatment, particularly among those with CD4 cell counts below 200 cells/µL, a well-established marker of immunodeficiency.

The most commonly identified pathogen is Trichophyton rubrum; however, an increasing diversity of emerging and potentially drug-resistant fungal species has also been reported. In addition, a characteristic clinical presentation—proximal nail involvement—is frequently observed, which may serve as an early clinical indicator of HIV infection.

The authors conclude that viral suppression through cART contributes to clinical improvement of the disease. Nevertheless, several issues require further clarification, as outlined below.

- It is acknowledged that CD4+ T-lymphocyte counts were only available for 123 out of 306 patients (40.2%), which limits the ability to adequately synthesize the relationship between immune status and infection. The authors are therefore encouraged to further elaborate on this limitation and discuss its implications in greater depth.

- While cases were reported globally, a substantial majority (85.8%) originated from the Americas. As the authors suggest, this distribution may reflect differences in diagnostic and reporting capacity rather than the true global prevalence. This point warrants further discussion and critical interpretation.

- With regard to Trichosporon spp. infections, it is noteworthy that lateral flow immunochromatographic assays may exhibit immunological cross-reactivity with Cryptococcus neoformans through detection of cell-wall glucuronoxylomannan (GXM). The authors should further elaborate on this aspect, particularly to highlight its diagnostic significance and potential implications.

- Table 1 should be revised. The rationale for the use of black shading in the topography column (Hand vs Foot) remains unclear, and the overall presentation appears overly complex. The authors may consider restructuring the table, for example by dividing it into Table 1.1 and Table 1.2, or by adopting an alternative format that enhances clarity and readability.

- The units used for CD4 cell counts are inconsistent throughout the manuscript, alternating between “cells/µL” and “cells/mm³”. A single standardized unit should be adopted consistently across the entire manuscript.

N/A

Author Response

Response to Reviewer 1 Comments.

We greatly appreciate the revisions made to our manuscript entitled “Relationship between onychomycosis and HIV: A systematic review.” by Cruz-López Samantha et al. We addressed the comments and suggestions from reviewers. These revisions have been of great help to round out and improve our work.

All the authors appreciate very much the opportunity to correct the manuscript, hoping it is suitable for acceptance and publication in your prestigious journal with these changes.

Looking forward to hearing from you shortly, best wishes

Point-by-point response to Comments and Suggestions for Authors

Comments 1: [It is acknowledged that CD4+ T-lymphocyte counts were only available for 123 out of 306 patients (40.2%), which limits the ability to adequately synthesize the relationship between immune status and infection. The authors are therefore encouraged to further elaborate on this limitation and discuss its implications in greater dept].

Response:

Thank you for taking the time to provide the observations for correction. The findings of this review highlight the importance of systematically including CD4+ T cell counts in future studies and reports that explore the potential relationship between onychomycosis and HIV-associated immunosuppression. The absence of this parameter limits the ability to establish a robust association, as the degree of immunosuppression is a determining factor in the susceptibility to and clinical presentation of opportunistic infections, including nail mycoses.

Furthermore, integrating CD4+ T cell counts would allow for a more precise correlation between the clinical manifestations of onychomycosis and the patient's immune status. This could help clarify whether certain clinical forms, extent, or severity of the disease are associated with specific levels of immunosuppression, which would be particularly relevant in populations with limited access to specialized immunological studies.

This limitation is discussed in more detail in the corresponding section(5. Limitations) of the text as follows:

Specifically, the limitation of the CD4 T lymphocyte count highlights the importance of systematically including the CD4+ T lymphocyte count in future studies/reports, as it would enable a more accurate correlation between the clinical manifestations of onychomycosis and the patient's immune status.

Comments 2: [While cases were reported globally, a substantial majority (85.8%) originated from the Americas. As the authors suggest, this distribution may reflect differences in diagnostic and reporting capacity rather than the true global prevalence. This point warrants further discussion and critical interpretation]

Response:

Thank you for your attention in correcting our details. However, this distribution should be interpreted with caution, as it likely reflects differences in diagnostic capacity, surveillance systems, and scientific output, rather than a true global epidemiology. In several countries in the Americas, there is greater access to mycological diagnostic tools, facilitating the identification of typical and atypical presentations of onychomycosis in people with HIV. Conversely, regions with a high prevalence of HIV infection, such as sub-Saharan Africa and parts of Asia, may be underrepresented due to limited diagnostic infrastructure, reduced access to specialized care, and a lack of reporting in indexed literature. Furthermore, publication bias may contribute to this pattern, as studies from the Americas are more frequently indexed in international databases. Therefore, the apparent predominance in this region likely represents a combination of improved detection, more thorough clinical follow-up, and a reporting mechanism.

This limitation is analyzed in more detail in the corresponding section (4. Discussion):

However, this distribution should be interpreted with caution, as it likely reflects differences in diagnostic capacity, surveillance systems, and scientific output, rather than a true global epidemiology. In several countries in the Americas, there is greater access to mycological diagnostic tools, facilitating the identification of typical and atypical presentations of onychomycosis in people with HIV. Conversely, regions with a high prevalence of HIV infection, such as sub-Saharan Africa and parts of Asia, may be underrepresented due to limited diagnostic infrastructure, reduced access to specialized care, and a lack of reporting in indexed literature. Furthermore, publication bias may contribute to this pattern, as studies from the Americas are more frequently indexed in international databases. Therefore, the apparent predominance in this region likely represents a combination of improved detection, more thorough clinical follow-up, and a reporting mechanism.

UNAIDS. Global HIV & AIDS Statistics — Fact Sheet 2024. Joint United Nations Programme on HIV/AIDS (UNAIDS). 2025. Disponible en: https://www.unaids.org/en/resources/fact-sheet

Comments 3: [With regard to Trichosporon spp. infections, it is noteworthy that lateral flow immunochromatographic assays may exhibit immunological cross-reactivity with Cryptococcus neoformans through detection of cell-wall glucuronoxylomannan (GXM). The authors should further elaborate on this aspect, particularly to highlight its diagnostic significance and potential implications].

Response:

Thank you for this observation, which we consider very important, and we have

already made the corresponding clarification in the article.

On the other hand, it should be clarified that the reported cases of Trichosporon spp. were carried out with automated system (VITEK and VITEK-2) ^(26,29) which is based on the biochemical profile, since it has been reported that this microorganism shares antigenic reactivity with Cryptococcus neoformans when the diagnosis of the latter is made by lateral flow immunochromatographic assays through detection of cell-wall glucuronoxylomannan (GXM), thus highlighting the importance of carrying out molecular biology studies in order to avoid this bias.

Ferreira EO, Mendes INVF, Monteiro SG, et al. Virulence properties and sensitivity profile of Candida parapsilosis complex species and Kodamaea ohmeri isolates from onychomycosis of HIV/AIDS patients. Microb Pathog. 2019;132:282-292. doi:10.1016/j.micpath.2019.05.012

Flores-Bozo LR, Méndez-Flores S, Olvera-Rodríguez V, et al. Nail Changes in People Living with Human Immunodeficiency Virus: Observational and Cross-Sectional Study in a Third-Level Hospital. Skin Appendage Disord. 2022;8(5):368-375. doi:10.1159/000524257

Fonseca FL, Frases S, Casadevall A, Fischman-Gompertz O, Nimrichter L, Rodrigues ML. Structural and functional properties of the Trichosporon asahii glucuronoxylomannan. Fungal Genet Biol. 2009;46(6–7):496–505. http://dx.doi.org/10.1016/j.fgb.2009.03.003

Comments 4: [Table 1 should be revised. The rationale for the use of black shading in the topography column (Hand vs Foot) remains unclear, and the overall presentation appears overly complex. The authors may consider restructuring the table, for example by dividing it into Table 1.1 and Table 1.2, or by adopting an alternative format that enhances clarity and readability].

Response:

Thank you for the opportunity to correct these details. The necessary corrections were made to the tables to facilitate clearer interpretation, integrating the columns for improved readability, and adding footnotes to the table that explain the meaning of the shading and abbreviations.

Comments 5: [The units used for CD4 cell counts are inconsistent throughout the manuscript, alternating between “cells/µL” and “cells/mm³”. A single standardized unit should be adopted consistently across the entire manuscript].

Response:

Thank you for pointing out these details. The units found like “cells/mm³” in page number 7, second paragraph, rows 269 and 275 were standardized to “cells/µL”.

Author Response File: Author Response.docx

Reviewer 2 Report

The authors conducted a systematic review to assess the association between onychomycosis and HIV, focusing on prevalence, clinical characteristics, causative agents, and CD4+ T-cell counts at diagnosis.

Line 77. Please, replace dot to comma.

Figure 1. Please, move text in the upper part so it become visible

Author Response

Response to Reviewer 2 Comments.

All the authors appreciate very much the opportunity to correct the manuscript, hoping it is suitable for acceptance and publication in your prestigious journal with these changes.

Looking forward to hearing from you shortly, best wishes

In red you will find the your comments, followed by the response.

Comments 1: [Line 77. Please, replace dot to comma.]

Response:

We appreciate the punctuation correction. The dot was replaced by a comma on the second page, third paragraph, on line 77.

Comments 2: Figure 1. [Please, move text in the upper part so it become visible]

Response:

You're right, the format doesn't allow the text to be read correctly, thank you for pointing that out. The text in figure one was adjusted to improve its visibility.

Author Response File: Author Response.docx

Reviewer 3 Report

This paper from Samantha Cruz-López and colleagues is a meta-analysis published papers about onychomycosis and patient living with HIV. The published literature on this subject is rather sparse and the authors included only 30 papers, 7 of which were case reports. As Spanish speakers they included papers in both English and Spanish, which is a plus. Papers from every continent except Australia were included. About half of the included cases came from a paper that used the All of US data base of patients who agreed to have their medical records entered into that data base. It has many advantages, but the participants are self-selected, which could introduce biases. One the other hand, case reports are generally published because they are oddities, so not usually included in a meta-analysis.

Comments for authors.

Table one is very busy and includes information about which foot/hand was involved. Unless there is a reason to believe that right or left makes a difference in pathogenesis, I would omit that.
I could not retrieve Reference 24 via Pub Med or on OFID website. Is it correct?
Onychomycosis is a dynamic process, and a case report is a single point in time, so I am not sure whether the number of digits involved is important, as in many patients the infection will spread to involve more digits over time.
The organisms isolated from the nails is interesting because some are unusual isolates, but there is no control of isolates from HIV negative patients in the same environments.
The lack of information about CD4 counts at the time of diagnosis limits the ability to know whether or not onychomycosis is really opportunistic infections, or if severity is inversely correlated with CD4 count.

Line 171 omit “In contrast…”

The paragraph beginning on line 185 is based on only 14 patients, mostly from single case reports so cannot be relied upon to provide unbiased data.

In the paragraph beginning on line 201 it is not clear whether these numbers were from the same sources as the preceding paragraph. If so, they are not reliable.

Author Response

Response to Reviewer 3 Comments.

All the authors appreciate very much the opportunity to correct the manuscript, hoping it is suitable for acceptance and publication in your prestigious journal with these changes.

Looking forward to hearing from you shortly, best wishes

In red you will find the your comments, followed by the response.

Comments 1: [This is essentially a meta-analysis that includes several case reports. Given publication bias it is impossible to say whether these cases establish that oychomycoses are more common or more severe in HIV+ individuals than matched controls. One was to help establish that is to show that severity is inversely correlated with CD4 counts, but they do not have that information.]

Response: We thank the reviewer for this insightful comment. We would like to clarify that the present study is not a meta-analysis, but a systematic review of published cases and case series, aimed at qualitatively synthesizing the clinical and microbiological characteristics of onychomycosis in people living with HIV. Therefore, our objective was not to establish causality relative to HIV-negative controls.

We have revised the manuscript to emphasize that our findings should be interpreted as descriptive rather than inferential, and that no conclusions regarding comparative risk can be drawn.

Regarding the reviewer’s suggestion to explore the relationship between severity and CD4 counts, we agree that this would be clinically relevant. However, most of the included reports did not consistently provide immunological parameters such as CD4 cell counts or standardized measures of disease severity, precluding a meaningful correlation analysis. We have now explicitly acknowledged this limitation in the discussion.

Finally, we have clarified that our study is intended to highlight clinical presentation, etiological agents, and diagnostic considerations in this population, rather than to quantify risk, which would require well-designed comparative or meta-analytic studies.

We thank the reviewer for this insightful and important comment. We would like to clarify that the present study is not a meta-analysis, as it does not include or quantitatively synthesize randomized or non-randomized clinical trials. Instead, it is a systematic, descriptive review of published case reports, case series, and observational studies, aimed at qualitatively summarizing the available clinical and microbiological evidence on onychomycosis in people living with HIV.

Furthermore, this work has a narrative component, as there are currently no prior studies that comprehensively synthesize the total number of reported cases and their clinical characteristics in this population. Given the lack of higher-level evidence and the absence of studies designed to systematically integrate this information, we considered it relevant to compile and analyze the available data to provide a clearer clinical overview.

We agree with the reviewer that publication bias is an inherent limitation when synthesizing case-based literature, as more severe or atypical presentations are more likely to be reported. This limits the ability to draw conclusions regarding disease frequency or severity in comparison with HIV-negative matched controls. Accordingly, we have revised the manuscript to emphasize that our findings are descriptive rather than inferential, and that no conclusions regarding comparative risk can be established.

Regarding the reviewer’s suggestion to explore a potential inverse relationship between disease severity and CD4 cell counts, we agree that this would be clinically meaningful. We attempted to assess whether CD4 levels might be associated with disease presentation, particularly at the time of diagnosis. However, the available data were highly heterogeneous and inconsistently reported, and most studies did not include standardized measures of severity or complete immunological parameters. As a result, it was not possible to establish a clear relationship or determine a specific threshold at which CD4 count becomes clinically relevant. We have now explicitly acknowledged this limitation in the discussion.

Finally, we have clarified that the primary aim of this study is to highlight the spectrum of clinical presentations, etiological agents, and diagnostic considerations in this population. We emphasize that future research, ideally involving well-designed comparative studies with standardized reporting of immunological markers and disease severity, will be necessary to better understand the potential relationship between HIV-associated immunosuppression and onychomycosis.

We wrote this limitation in the corresponding section:

During this review, a limitation in the epidemiological analysis was found due to a considerable lack of data, particularly regarding CD4+ T cell count, age, sex, number of affected nails, and antiretroviral treatment status, which prevented consistent comparisons. This is a descriptive study; therefore, we cannot establish direct associations but rather report the findings available in the literature, highlighting the spectrum of clinical presentations, etiological agents, and diagnostic considerations in this population. Specifically, the limitation of the CD4 T lymphocyte count highlights the importance of systematically including the CD4+ T lymphocyte count in future studies/reports, as it would enable a more accurate correlation between the clinical manifestations of onychomycosis and the patient's immune status. Likewise, information on antifungal treatment and its outcomes was incomplete, hindering the evaluation of therapeutic efficacy. This underscores the need for greater precision and standardization in reporting information in these patients to enable more accurate assessments in future studies.

Comments 2: [Table one is very busy and includes information about which foot/hand was involved. Unless there is a reason to believe that right or left makes a difference in pathogenesis, I would omit that.]

Response: Thank you, we agree that laterality (right vs. left) does not directly influence the pathogenesis of onychomycosis. However, we opted to retain this information because it may provide clinically relevant context in cases of mixed or multifocal onychomycosis, where different nails, even within the same patient, can be affected by distinct fungal species or present varying clinical patterns.

In this regard, documenting the specific location of involvement allows a more precise correlation between clinical presentation and microbiological finding, particularly in reports describing multiple isolates or co-infections.

We have, however, revised and modified Table 1 to improve its clarity.

This phenomenon has been reported and explained in previous studies:

Rodríguez-Cerdeira C, Martínez-Herrera E, Cortés-López PN, et al. Fungal Melanonychia: A Systematic Review. Microorganisms. 2024;12(6):1096. Published 2024 May 28. doi:10.3390/microorganisms12061096

Comments 3: [I could not retrieve Reference 24 via Pub Med or on OFID website. Is it correct?]

Response: The abstract can be found on PubMed at the following link https://pubmed.ncbi.nlm.nih.gov/26155930/.

Comments 4: [Onychomycosis is a dynamic process, and a case report is a single point in time, so I am not sure whether the number of digits involved is important, as in many patients the infection will spread to involve more digits over time.]

Response: We agree that onychomycosis is a dynamic process that may progress to additional digits over time. However, we consider the number of affected digits at the time of evaluation to be clinically relevant, as it provides a characterization of disease extent and severity. In the context of case reports and case series, this variable reflects the stage at which the disease was documented and may help identify patterns of presentation according to the extent of involvement.

Comments 5: [The organisms isolated from the nails is interesting because some are unusual isolates, but there is no control of isolates from HIV negative patients in the same environments.]

Response: We appreciate your comment; However, it is important to emphasize that this systematic review focuses exclusively on establishing the relationship between people living with HIV and onychomycosis, although there are reports of onychomycosis in other populations without HIV, they are not the purpose of this study, since the objective is to standardize and define its correlation with the degree of immunodeficiency, as well as to define the sociodemographic characteristics described in the existing literature.

Comments 6: [The lack of information about CD4 counts at the time of diagnosis limits the ability to know whether or not onychomycosis is really opportunistic infections, or if severity is inversely correlated with CD4 count.]

Response: The findings of this review highlight the importance of systematically including CD4+ T cell counts in future studies and reports that explore the potential relationship between onychomycosis and HIV-associated immunosuppression. The absence of this parameter limits the ability to establish a robust association, as the degree of immunosuppression is a determining factor in the susceptibility to and clinical presentation of opportunistic infections, including nail mycoses. Furthermore, integrating CD4+ T cell counts would allow for a more precise correlation between the clinical manifestations of onychomycosis and the patient's immune status. This could help clarify whether certain clinical forms, extent, or severity of the disease are associated with specific levels of immunosuppression, which would be particularly relevant in populations with limited access to specialized immunological studies.

This limitation is discussed in more detail in the corresponding section of the text.

Comments 7: [Line 171 omit “In contrast…”]

Response: Thank you for your correction, the phrase "in contrast" was removed from line 171 on page 5, third paragraph.

Comments 8: [The paragraph beginning on line 185 is based on only 14 patients, mostly from single case reports so cannot be relied upon to provide unbiased data.]

Response: Thank you for your attention in allowing us to make the necessary corrections. We would like to emphasize that this study is a systematic review, and as such, it is methodologically appropriate to include and synthesize evidence from case reports and small case series. We agree that the paragraph in question is based on a limited number of patients (n=14), primarily derived from individual case reports, and therefore is subject to selection and publication bias. As such, these findings should not be interpreted as providing robust or generalizable evidence.

We clarify that this information is presented as a descriptive observation intended to highlight potential clinical patterns rather than to draw definitive conclusions. We have also explicitly acknowledged the limitations related to small sample size and potential bias in this subset of data.

Comments 9: [In the paragraph beginning on line 201 it is not clear whether these numbers were from the same sources as the preceding paragraph. If so, they are not reliable.]

Response: We understand your concern and this paragraph discusses other cases different from the previous one; however, it is important to clarify that this is a systematic review in which we can include the case reports described in this paragraph.

This paragraph includes 9 studies (8 case reports and one case series) with a total of 14 patients in which the way in which the diagnosis was made is described: 11(78.5%) of them through direct examination with potassium hydroxide and culture, 1(7.1%) patient with direct examination with potassium hydroxide, culture and molecular tests, 1(7.1%) patient with direct examination with potassium hydroxide, culture and biopsy and finally 1(7.1%) patient with biopsy, culture and molecular tests.

Author Response File: Author Response.docx

Reviewer 4 Report

Dear editor and authors,

I’ve read and carefully evaluated Your manuscript ,,Relationship Between Onychomycosis and HIV: A Systematic Review’’

The topic of the relationship between onychomycosis and HIV infection is relevant and of clinical interest. While similar reviews exist, the manuscript attempts to synthesize dispersed data, which adds important value. In my opinion, in the current form the manuscript needs a major revision.

Major revision is required before the manuscript can be considered for publication

Regards,

Introduction

The Introduction provides useful background, however:

some sentences are overly complex and could be simplified for clarity, for example:

,,The relationship between HIV and onychomycosis involves complex interactions…”

Minor typographical issues are present (e.g., ,,Inequelities”, line 56), which should be corrected.

--> Improve readability by simplifying long sentences and carefully proofreading the section

Materials and methods

,,studies without significant results” were excluded--> This introduces systematic bias, as exclusion based on significance is not acceptable in systematic reviews. Remove this criterion or provide strong methodological justification.
Figure 1 has to be corrected as a part of the text is missing in a few places.
You note heterogeneity in reported variables, but do not explain how was this handled analytically.

,,CD4 T-lymphocyte count was reported heterogeneously…”

Results

It is unclear how the subset (306 patients) relates to the full dataset (1,296 patients).

,,Thirty articles met the inclusion criteria: case reports (n=7) [16-22], one case series (n=1) [23], and observational studies (n=22) [24–45], comprising 1,296 patients (Table 2)’’

And then

,,Seven case reports [16–22], one case series [23], and ten observational studies [24, 26, 152 27, 29, 32, 35, 37, 39, 40, 42] included a detailed description of diagnosed patients, comprising a total of 306 individuals.’’

Please, clearly distinguish full dataset and subset used for detailed analysis. It is not sufficiently clear how these datasets are related.

Interpretative statements as ,,which likely reflects greater diagnostic and reporting capacity” are more appropriate for the Discussion.

Discussion

The conclusion regarding immunosuppression ,,predominance of advanced immunosuppression…” is based on incomplete data (CD4 available only for a subset) so it should be clearly stated.
There is a minor inconsistency: treatment analysis ,,was not included in the primary objective” while treatment is still discussed in detail.

--> Align conclusions with data completeness and ensure consistency between objectives and presented analyses

Coclusions

The Conclusions summarize the findings clearly, however:

The statement ,,onychomycosis is a frequent and clinically significant manifestation in people with HIV” may be too strong given that no formal prevalence analysis was conducted.

--> Rephrase to better reflect the descriptive nature and limitations of the included studies.

Other comments:

Correct typographical and encoding errors
Ensure consistent formatting of species names (Candida spp., Trichophyton rubrum)
Review the study with PRISMA Checklist in mind
Tables 1 and 2 are broken and in this form they can’t be read easily

Overall:

The manuscript addresses an important topic and has the potential to contribute to the field. However, due to:

concerns regarding methodological rigor
incomplete and heterogeneous data reporting
overinterpretation of results

Author Response

Response to Reviewer 4 Comments.

All the authors appreciate very much the opportunity to correct the manuscript, hoping it is suitable for acceptance and publication in your prestigious journal with these changes.

Looking forward to hearing from you shortly, best wishes

In red you will find the your comments, followed by the response.

Introduction.

Comments 1: [The Introduction provides useful background, however: some sentences are overly complex and could be simplified for clarity, for example: ,,The relationship between HIV and onychomycosis involves complex interactions…”

Response: We thank the reviewer for this valuable observation. We agree that some sentences in the Introduction were overly complex and could affect clarity. Accordingly, we have revised the section to improve readability by simplifying sentence structure, reducing redundancy, and dividing longer statements into shorter, more precise sentences.

In particular, we have rephrased sentences such as “The relationship between HIV and onychomycosis involves complex interactions…” to present the concepts in a clearer and more concise manner, while preserving the original meaning and without adding new information.

These revisions were applied throughout the Introduction to enhance clarity and ensure a more direct and accessible presentation of the background.

Comments 2: Minor typographical issues are present (e.g., ,,Inequelities”, line 56), which should be corrected. --> Improve readability by simplifying long sentences and carefully proofreading the section.]

Response: Thank you for your time, we have reviewed and modified the wording to be appropriate, we change the phrase health system inequalities for poor access to health services in line 56.

Materials and methods.

Comments 3: [,,studies without significant results” were excluded--> This introduces systematic bias, as exclusion based on significance is not acceptable in systematic reviews. Remove this criterion or provide strong methodological justification.]

Response: We agree with and appreciate your observation. The article included in that exclusion criterion also lacked complete information on the variables we studied, so it was moved to the corresponding exclusion category, "incomplete information," and the wording regarding that methodology was modified in the text.

Comments 4: [Figure 1 has to be corrected as a part of the text is missing in a few places.]

Response: Thank you. We made the necessary modifications to the image for the text display, thank you.

Comments 5: [You note heterogeneity in reported variables, but do not explain how was this handled analytically “,,CD4 T-lymphocyte count was reported heterogeneously…”]

Response: Thank you for your analysis. We have already homogenized the data; however, it should be clarified that cells/mm³ or cells/µL are equivalent units of measurement, so they can be used interchangeably in the CD4 T lymphocyte count report.

Comments 6: [It is unclear how the subset (306 patients) relates to the full dataset (1,296 patients). ,,Thirty articles met the inclusion criteria: case reports (n=7) [16-22], one case series (n=1) [23], and observational studies (n=22) [24–45], comprising 1,296 patients (Table 2)’’ And then ,,Seven case reports [16–22], one case series [23], and ten observational studies [24, 26, 152 27, 29, 32, 35, 37, 39, 40, 42] included a detailed description of diagnosed patients, comprising a total of 306 individuals.’’ Please, clearly distinguish full dataset and subset used for detailed analysis. It is not sufficiently clear how these datasets are related.]

Response: We thank the reviewer for this important observation. We agree that the distinction between the full dataset (n=1,296) and the subset used for detailed analysis (n=306) was not sufficiently clear in the original manuscript.

To clarify, the full dataset (n=1,296) includes all patients reported across the 30 studies that met the inclusion criteria and was used to describe overall study characteristics and general trends. However, only a subset of these studies (7 case reports, 1 case series, and 10 observational studies), comprising 306 patients, provided individual-level or sufficiently detailed clinical and microbiological data, which allowed for a more in-depth descriptive analysis.

We have revised the manuscript to explicitly distinguish between these two datasets and to clarify that the detailed analysis was restricted to studies with adequate granularity of reported data in line 155, page 5, second paragraph.

Comments 7: [Interpretative statements as ,,which likely reflects greater diagnostic and reporting capacity” are more appropriate for the Discussion.]

Response: Thank you, the line you quote was rewritten in the discussion.

The incidence of onychomycosis in immunocompromised patients is increasing; in people living with HIV, this clinical entity represents one of the early manifestations of infection, with a prevalence ranging from 15% to 40%, approximately four times higher than in the general population. [18, 22, 32, 35, 41] Our results suggest a predominance of cases in the Americas [85.8% (n=112)], particularly in the United States [64.2% (n=833)], followed by Mexico [6.4% (n=83)] and Brazil [4.1% (n=54)], which likely reflects greater diagnostic and reporting capacity.

Discussion

Comments 8: [The conclusion regarding immunosuppression ,,predominance of advanced immunosuppression…” is based on incomplete data (CD4 available only for a subset) so it should be clearly stated.]

Response: We appreciate your observation; however, this inference is made with the information reported in the literature to date, and with it, we seek to emphasize the importance of including this parameter in future reports to increase its sensitivity in patients living with HIV who present with onychomycosis. Therefore, we cannot say that the information we included is incomplete, since, as we reiterate, all available information was included. Se agregó al finalizar realizar reportes con información estandarizada de cada paciente

Comments 9: [There is a minor inconsistency: treatment analysis ,,was not included in the primary objective” while treatment is still discussed in detail. Align conclusions with data completeness and ensure consistency between objectives and presented analyses.]

Response: We understand your concern; however, the mention of the limited information available regarding the treatment of onychomycosis in patients living with HIV was made solely to emphasize, in general terms, the lack of research in this area and the absence of an established standard of care. It was not included as a study objective, as this topic was not explored in depth, nor was the treatment received by the patients analyzed; therefore, we considered it pertinent to make this clarification.

Conclusion

Comments 10: [The statement ,,onychomycosis is a frequent and clinically significant manifestation in people with HIV” may be too strong given that no formal prevalence analysis was conducted. Rephrase to better reflect the descriptive nature and limitations of the included studies.]

Response: We thank the reviewer for this important observation. We agree that the original statement may overestimate the strength of the evidence, given the absence of formal prevalence data and the descriptive nature of the included studies. Accordingly, we have revised the sentence to better reflect that our findings are based on reported cases and do not allow estimation of frequency or clinical burden at the population level.

This systematic review confirms that onychomycosis is a clinical condition reported in people living with HIV, although its frequency and overall clinical impact cannot be determined from the predominantly descriptive and case-based literature. This gap limits understanding of the disease burden, the natural history of onychomycosis in HIV, and appropriate therapeutic strategies.

Other comments:

Comments 11: [Correct typographical and encoding errors.]

Response: We appreciate your feedback and are pleased to inform you that a thorough review of the entire text was carried out, where typographical errors were properly corrected and footnotes were added to the reported tables.

Comments 12: [Ensure consistent formatting of species names (Candida spp., Trichophyton rubrum)]

Response: We appreciate your point of view, allow me to clarify that, in this review, the scientific names of etiological agents were used as reported in the reviewed articles; however, according to the 2017 nomenclature, some have changed due to polyphasic studies (macro and microscopies, biochemical analysis, secondary metabolites, and molecular biology).

McNeill J, Barrie FR, Buck WR, et al. International Code of Nomenclature for algae, fungi, and plants (Shenzhen Code). Regnum Veg. 2018;159.

Comments 13: [Review the study with PRISMA Checklist in mind.]

Response: We appreciate your feedback and want you to know that the PRISMA scheme checklist was completed to ensure proper compliance with the study format.

Comments 14: [Tables 1 and 2 are broken and in this form they can’t be read easily]

Response: Thanks for the observation, the tables were already structured to facilitate the reading of the data.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

- Please check details in the Table 1. Regarding, E.pydermophyton floccosum, T.richophyton mentagrophytes ??

- As this manuscript includes numerous scientific names of different fungal species, the authors should carefully review and ensure that all such names are consistently formatted in italics throughout.

N/A

Author Response

All the authors appreciate very much the opportunity to correct the manuscript, hoping it is suitable for acceptance and publication in your prestigious journal with these changes.

Looking forward to hearing from you shortly, best wishes

Point-by-point response to Comments and Suggestions for Authors

Response to Reviewer 1 Comments.

Comments 1. Please check details in the Table 1. Regarding, E.pydermophyton floccosum, T.richophyton mentagrophytes ??

Response. We appreciate the thorough review that was carried out, which allows us to correct these nomenclature errors, which you will be able to see properly written in the table like Epydermophyton floccosum and Trichophyton mentagrophytes.

Comments 2. As this manuscript includes numerous scientific names of different fungal species, the authors should carefully review and ensure that all such names are consistently formatted in italics throughout.

Response. We understand your review and appreciate your urging us to conduct this review so that we can correct the names of fungal species appropriately.

Author Response File: Author Response.pdf

Reviewer 3 Report

This paper by Samantha Cruz-López is a resubmission. The paper is improved but there are a few issues that should be addressed.

On line 200 they give they added the percentage of each sex in the reports; it is no necessary to include both sexes as it has to add up to 100% They don’t comment on that but considering that in North American HIV is primarily a disease of men, it is not surprising that men account for 70% of their reported cases. Heterosexual transmission of HIV is more common in Africa. Were the women from the 2 African studies? Sub-Saharan
The paragraph beginning on line 346 is confusing and irrelevant and should be deleted. It implies that a microbiology lab might misidentify Trichosporon as Cryptococcus because the GXM from the former is structurally related to that of the latter, and will react with the commercial antibodies that are widely used to diagnose cryptococcal infection. Trichosporon are yeast that produce segmented hyphae that contain arthroconidia. Cryptococci reproduce by budding. Furthermore, Vitek and Vitek2 are not molecular methods for identifying organisms, they are automated biochemical tests. They often misidentify Trichosporon. It is not inconceivable that a sever case of Trichsporon onychomycosis might cause a “false positive” serum Cryptococcal antigen result, but I have not seen a report of that.
In the paragraph starting on line 302 that authors rightly note that there are a number of patients with preserved CD4 counts that have onychomycosis, but this should not be surprising as most cases of onychomycosis occur in patients with normal immune systems. I don’t think anyone believes that onychomycosis is an opportunistic infection.
Why is reference 41 not included in table 1?
I still think table 1 is to busy and that there is no reason to think that it is of any importance which foot or hand was involved. Since these infections are slowly progressive, the number of digits involved at the time of the case report is also of no importance unless you know how long the patient was infected so you could infer differences in rate of spread.
The lack of HIV negative controls from the same geographic areas as the HIV+ controls makes it impossible to know whether PLHIV are more likely to be infected with unusual fungi. I suspect that in most countries people will not seek medical care for onychomycoses so this could be a hard study to do.

This paper by Samantha Cruz-López is a resubmission. The paper is improved but there are a few issues that should be addressed.

On line 200 they give they added the percentage of each sex in the reports; it is no necessary to include both sexes as it has to add up to 100% They don’t comment on that but considering that in North American HIV is primarily a disease of men, it is not surprising that men account for 70% of their reported cases. Heterosexual transmission of HIV is more common in Africa. Were the women from the 2 African studies? Sub-Saharan
The paragraph beginning on line 346 is confusing and irrelevant and should be deleted. It implies that a microbiology lab might misidentify Trichosporon as Cryptococcus because the GXM from the former is structurally related to that of the latter, and will react with the commercial antibodies that are widely used to diagnose cryptococcal infection. Trichosporon are yeast that produce segmented hyphae that contain arthroconidia. Cryptococci reproduce by budding. Furthermore, Vitek and Vitek2 are not molecular methods for identifying organisms, they are automated biochemical tests. They often misidentify Trichosporon. It is not inconceivable that a sever case of Trichsporon onychomycosis might cause a “false positive” serum Cryptococcal antigen result, but I have not seen a report of that.
In the paragraph starting on line 302 that authors rightly note that there are a number of patients with preserved CD4 counts that have onychomycosis, but this should not be surprising as most cases of onychomycosis occur in patients with normal immune systems. I don’t think anyone believes that onychomycosis is an opportunistic infection.
Why is reference 41 not included in table 1?
I still think table 1 is to busy and that there is no reason to think that it is of any importance which foot or hand was involved. Since these infections are slowly progressive, the number of digits involved at the time of the case report is also of no importance unless you know how long the patient was infected so you could infer differences in rate of spread.
The lack of HIV negative controls from the same geographic areas as the HIV+ controls makes it impossible to know whether PLHIV are more likely to be infected with unusual fungi. I suspect that in most countries people will not seek medical care for onychomycoses so this could be a hard study to do.

Author Response

All the authors appreciate very much the opportunity to correct the manuscript, hoping it is suitable for acceptance and publication in your prestigious journal with these changes.

Looking forward to hearing from you shortly, best wishes

Point-by-point response to Comments and Suggestions for Authors

Response to Reviewer 3 Comments.

Comments 1. On line 200 they give they added the percentage of each sex in the reports; it is no necessary to include both sexes as it has to add up to 100% They don’t comment on that but considering that in North American HIV is primarily a disease of men, it is not surprising that men account for 70% of their reported cases. Heterosexual transmission of HIV is more common in Africa. Were the women from the 2 African studies? Sub-Saharan

Response: We thank the reviewer for this observation. As suggested, we have removed the redundant reporting of percentages for both sexes in the revised manuscript. Although Akinboro et al. and Claessens et al. (studies conducted in Africa) report a predominance of female participants, we consider it inappropriate to make a definitive assertion in this regard. This is because, within the subset of patients living with HIV with onychomicosis, these studies do not consistently specify sex-disaggregated data. Therefore, we have refrained from drawing conclusions about the geographic distribution of female cases to avoid overinterpretation

Comments 2. The paragraph beginning on line 346 is confusing and irrelevant and should be deleted. It implies that a microbiology lab might misidentify Trichosporon as Cryptococcus because the GXM from the former is structurally related to that of the latter, and will react with the commercial antibodies that are widely used to diagnose cryptococcal infection. Trichosporon are yeast that produce segmented hyphae that contain arthroconidia. Cryptococci reproduce by budding. Furthermore, Vitek and Vitek2 are not molecular methods for identifying organisms, they are automated biochemical tests. They often misidentify Trichosporon. It is not inconceivable that a sever case of Trichsporon onychomycosis might cause a “false positive” serum Cryptococcal antigen result, but I have not seen a report of that.
Response: We appreciate and understand your observation; in fact, this paragraph was not in the original text. However, during the first revision, we were asked, in one of the corrections, to include a paragraph explaining this situation, so we cannot remove this paragraph, although we appreciate your observation and we regret that we cannot follow this suggestion.

Comments 3. In the paragraph starting on line 302 that authors rightly note that there are a number of patients with preserved CD4 counts that have onychomycosis, but this should not be surprising as most cases of onychomycosis occur in patients with normal immune systems. I don’t think anyone believes that onychomycosis is an opportunistic infection.
Response. We appreciate your comment and agree that onychomycosis is not considered an opportunistic infection, as it predominantly occurs in immunocompetent individuals. We also acknowledge that cases with preserved CD4 counts are expected and do not contradict current understanding of the disease. However, in the context of our systematic review, CD4 count was included as an epidemiological parameter to characterize better the population of patients living with HIV and to explore potential variations in clinical presentation, severity, or outcomes across different levels of immune status. Therefore, its inclusion aims to provide a more comprehensive epidemiological description rather than to suggest an opportunistic nature of onychomycosis.

Comments 4. Why is reference 41 not included in table 1?
Response. Thank you for your observation regarding the bibliography corresponding to number 41. It was not included in Table 1 because the information in that article was insufficient to complete most of the developed items in the table; therefore, this reference was included in Table 2.

Comments 5. I still think table 1 is too busy and that there is no reason to think that it is of any importance which foot or hand was involved. Since these infections are slowly progressive, the number of digits involved at the time of the case report is also of no importance unless you know how long the patient was infected so you could infer differences in rate of spread.
Response. We appreciate and understand the observation, and we have therefore tried to summarize this section in the new table. However, we were unable to remove the item indicating whether the onychomycosis affects the hands and/or feet, as well as the number of affected nails, because in the first review, another reviewer asked us to indicate this item properly. We hope that with the modifications made, it can be accepted

Comments 6. The lack of HIV negative controls from the same geographic areas as the HIV+ controls makes it impossible to know whether PLHIV are more likely to be infected with unusual fungi. I suspect that in most countries people will not seek medical care for onychomycoses so this could be a hard study to do.

We thank you for this important observation. We fully acknowledge that, in the absence of HIV-negative control groups from the same geographic regions, it is not possible to establish whether people living with HIV are more likely to be infected with unusual fungal species. We also agree that conducting such comparative studies would be methodologically challenging, particularly given that many patients with onychomycosis do not seek medical care, which may introduce significant selection bias.

In our manuscript, we do not make a definitive assertion in this regard. Rather, we report the findings as described in the included studies, reflecting the available evidence without inferring causality. We will revise the text to clarify further that these observations are descriptive and should be interpreted with caution.

Author Response File: Author Response.pdf

Reviewer 4 Report

The authors responded positively to the reviewers' suggestions; the article requires only minor editorial corrections and graphical corrections are to be considered.

Please follow the italics in the text for the species (Cryptococcus neoformans) (349)

Author Response

All the authors appreciate very much the opportunity to correct the manuscript, hoping it is suitable for acceptance and publication in your prestigious journal with these changes.

Looking forward to hearing from you shortly, best wishes

Point-by-point response to Comments and Suggestions for Authors

Response to Reviewer 4 Comments.

Comments . The article requires only minor editorial corrections and graphical corrections are to be considered.

Thank you for your feedback. The tables have been modified to improve the article's presentation.

Comments 2. Please follow the italics in the text for the species (Cryptococcus neoformans) (349)

Thank you for your observation. We've corrected it by italicizing the microorganism's name on line 349, page two, paragraph.

Author Response File: Author Response.pdf