PONE-D-19-29695

Role of CD4/CD8 ratio on the incidence of tuberculosis in HIV-infected patients on antiretroviral therapy followed up for more than a decade

PLOS ONE

Dear Wolday

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.

==============================The longitudinal aspect of the study is its strength, yet the analysis presented in the manuscript is essentially a cross-sectional analysis, so misses the opportunity to better understand if low CD4/CD8 ratio is an early predictor of future TB risk, vs instead just a reflection of Mtb-mediated immunosupression around time of presentation with active TB.  Probably the answer is a mix of both, but the results as presented miss an important opportunity. The authors need to address this critical point. 

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PLOS ONE

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Reviewers' comments:

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Reviewer #1: Yes

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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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: There have been several studies reported on the possibility of using CD4/CD8 ratio as a clinical tool to evaluate patients' immune status.

It has already been well established that a persistently lower CD4/CD8 ratio during otherwise effective antiretroviral therapy is associated with increased innate and adaptive immune activation and immunosenescent phenotype, thereby leading to increased risk of morbidity and mortality.

The study though being retrospective, and has followed up a cohort of HIV infected individuals for more than a decade, suffers from several limitations such as the inconsistency in the method of TB diagnosis which is very critical for this study's objective and the literature review could have been wider.

Reviewer #2: This manuscript describes a retrospective study of adults who started ART between 2001 and 2007 and were followed for a median of 11.5 years, including periodic assessments of CD4 & CD8. The underlying hypothesis was that PLWH on ART with low CD4/CD8 ratios were more likely to be diagnosed with incident TB than their counterparts with higher CD4/CD8. Key findings included a low overall TB incidence rate (1.44/100 py) and that CD4/CD8 < 0.3 at the time of TB diagnosis was significantly associated with incident TB in multivariate analysis.

Major Comments

1. As written, the manuscript focuses on immunologic profiles at the time of incident TB diagnosis-- thus the analysis appears to mainly be cross-sectional and not include the longitudinal data. The longitudinal data are a real strength of the study, and are essential for understanding whether persistently low CD4/CD8 over time is a risk factor (and perhaps marker for) future TB. This is a missed opportunity.

2. Isoniazid preventive therapy is not included as a variable in analyses of TB risk, yet has been shown by other groups to strongly influence development of future TB. The Methods section states that all participants were offered IPT and the Discussion section states that all patients received IPT. Nevertheless, it would be unusual for IPT uptake or adherence to be 100%. If uptake/adherence data are available, their inclusion in analyses of TB risk is recommended. If uptake/adherence data are not available, then this should be so indicated in the Discussion and presented as a potential weakness.

3. The Discussion, lines 331-333, states that there was “no difference in TB incidence rate between those who achieved viral suppression vs. those who did not.” However, data are provided only for the overall group and the group who achieved viral suppression. Please either provide data and statistics for the comparison of those who achieved vs did not achieve viral suppression, or revise the Discussion sentence.

Minor Comments

1. The Discussion mentions that data collection was retrospective. This important design feature should be clearly indicated in the Abstact and in the Methods section.

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Reviewer #1: No

Reviewer #2: No

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Role of CD4/CD8 ratio on the incidence of tuberculosis in HIV-infected patients on antiretroviral therapy followed up for more than a decade

PONE-D-19-29695R1

Dear Dr. Wolday

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Alan Landay

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 #3: 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 #3: Yes

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

Reviewer #1: Yes

Reviewer #3: 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 #3: 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 #3: 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: The comments have been appropriately addressed by the authors and the manuscript has been revised accordingly.

Reviewer #3: We appreciate your time responding to the comments from the initial review. The revised figures enhance the papers presentation.

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7. PLOS authors have the option to publish the peer review history of their article (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 #3: No