PONE-D-21-40508Impact of GeneXpert on TB Diagnosis and Anti-TB Treatment Outcome at Health Facilities in Addis Ababa, Ethiopia: In the Post MDG YearsPLOS ONE

Dear Dr. Getahun,

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.

==============================

This manuscript has potential value but there are​ major issues which should be addressed. There needs to be extensive English language editing including ensuring terminology like the references to the geneXpert are correct. In addition, there was some concern that the treatment outcomes were the incorrect measure of utility.The authors should also defined how they assess sensitivity and specificity performance

==============================

Please submit your revised manuscript by May 27 2022 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.

Please include the following items when submitting your revised manuscript:

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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,

Elizabeth S. Mayne, M.D.

Academic Editor

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?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Overall comments

1. The manuscript doesn’t read well so I suggest scientific editing. Word usage is incorrect eg. In the abstract, GeneXpert is described as an effective molecular diagnostic test, yet the GeneXpert is an analyzer, not a test.

2. Some sentences are too long and difficult to follow eg. Sentence 2 in the Background section.

Specific comments

1. Background:

a. Second paragraph, Line 4: Not sure how “acceptable” and “excellent” descriptions for the sensitivity and specificity were assigned. Please clarify.

b. Second paragraph, line 8: is the word “TB” supposed to follow the word “paucibacillary?”

2. Study design and data collection

a. Line 8: Five health centres were excluded due to refusal – not sure what this refers to.

3. Demographics and clinical characteristics of study participant on anti-TB treatment

a. First paragraph is a repetition of information provided in the “Study design and data collection” section

b. Was the Xpert MTB/RIF assay used to diagnose pTB as well as EPTB?

c. The conclusion reached is that the number of patients who started TB treatment increased due to introduction of the Xpert MTB/RIF assay but its not clear how many patients were also started on treatment due to other reasons e.g. positive culture or clinical case definitions? Was this assessed?

Reviewer #2: The authors have reviewed retrospective data since the implementation of the Xpert assay for TB diagnosis at participating facilities in Addis Ababa. The aim was to determine the impact of Xpert on TB diagnosis compared to smear microscopy, which is expected as the sensitivity far exceeds that microscopy. Secondly, they further assessed the impact on treatment outcomes since the introduction of the technology - measuring the impact is vague as there are several other factors to be considered for treatment outcome and attributing outcomes to a diagnostic may not be the conclusive. The authors should have rather assessed impact on treatment initiation rather than outcome. The focus of the papers starts shifting between different variables not specifically linked to the Xpert testing. The paper structure needs review to improve the flow of information to provide the supporting evidence showing the impact of Xpert on both TB diagnosis and treatment outcomes.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-40508R1Impact of GeneXpert on TB Diagnosis and Anti-TB Treatment Outcome at Health Facilities in Addis Ababa, Ethiopia: In the Post MDG Years

PLOS ONE

Dear Dr. Getahun,

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.

==============================

A number of improvements have been made in response to the reviewers queries. There are, however, still some significant issues which require clarification.

1. The introduction speaks of the ability of the GeneXpert to detect rifampicin resistance but these data are not included and it is unclear how the presence of RR is correlated with other measures. This is a serious flaw throughout the manuscript.

2. The methodology is incomplete - please discuss the specimens utilised (especially for the 0-14 age range) - were gastric washings, urine, blood and other samples included or just sputa. What was the failure rate of the equipment and what controls and monitoring were run. What was the reflex testing for culture and did any samples test positive on culture but negative on microscopy or geneXpert. What was the clinical correlation in these cases. 

3. Treatment outcome is defined as successful if the patient was cured or the treatment was completed. Please clarify how "cure" was defined in the 27.3% of patients who were cured. In the high number of individuals who completed treatment only, what was the outcome if they were not cured? What is the definition of treatment failure (were they bacteriologically still positive

4. The age range is suggestive of an economically active population. Was there any association with economic activity. The HIV statistics should be clarified in the context of the Ethiopian statistics as well.

5. Please change HIV reactive and unreactive to infected. Please also indicate where known whether patients were virologically suppressed or on ART (if known) and indicate whether this has a relationship to treatment outcome.

6. Please confirm what transfer in indicates

7. Were all treated patients and retreated patients on a standard 6 month regimen? If not, how many were on second line therapy. Were these patients admitted?

8. The following should be included in the discussion: why was there a slight male preponderance, can you hypothesise as to the age spread, can you comment on the efficacy of the test, can you comment on the acuracy of the test, can you link treatment response to HIV status, is there any other comorbid condition (diabetes, hypertension, obesity, cancer etc) which may explain the results. If these data are not available, that represents a significant limitations which should be addressed. In short there is a lack of explanation of the relevant findings which must be addressed.

A minor comment is that the manuscript still requires significant English language editing.

Please submit your revised manuscript by Feb 24 2023 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.

Please include the following items when submitting your revised manuscript:

• 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

A number of improvements have been made in response to the reviewers queries. There are, however, still some significant issues which require clarification.

1. The introduction speaks of the ability of the GeneXpert to detect rifampicin resistance but these data are not included and it is unclear how the presence of RR is correlated with other measures. This is a serious flaw throughout the manuscript.

2. The methodology is incomplete - please discuss the specimens utilised (especially for the 0-14 age range) - were gastric washings, urine, blood and other samples included or just sputa. What was the failure rate of the equipment and what controls and monitoring were run. What was the reflex testing for culture and did any samples test positive on culture but negative on microscopy or geneXpert. What was the clinical correlation in these cases.

3. Treatment outcome is defined as successful if the patient was cured or the treatment was completed. Please clarify how "cure" was defined in the 27.3% of patients who were cured. In the high number of individuals who completed treatment only, what was the outcome if they were not cured? What is the definition of treatment failure (were they bacteriologically still positive

4. The age range is suggestive of an economically active population. Was there any association with economic activity. The HIV statistics should be clarified in the context of the Ethiopian statistics as well.

5. Please change HIV reactive and unreactive to infected. Please also indicate where known whether patients were virologically suppressed or on ART (if known) and indicate whether this has a relationship to treatment outcome.

6. Please confirm what transfer in indicates

7. Were all treated patients and retreated patients on a standard 6 month regimen? If not, how many were on second line therapy. Were these patients admitted?

8. The following should be included in the discussion: why was there a slight male preponderance, can you hypothesise as to the age spread, can you comment on the efficacy of the test, can you comment on the acuracy of the test, can you link treatment response to HIV status, is there any other comorbid condition (diabetes, hypertension, obesity, cancer etc) which may explain the results. If these data are not available, that represents a significant limitations which should be addressed. In short there is a lack of explanation of the relevant findings which must be addressed.

A minor comment is that the manuscript still requires significant English language editing.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

[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. Please note that Supporting Information files do not need this step.

PONE-D-21-40508R2Impact of GeneXpert on TB Diagnosis and Anti-TB Treatment Outcome at Health Facilities in Addis Ababa, Ethiopia: In the Post MDG YearsPLOS ONE

Dear Dr. Getahun,

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.

This manuscript still requires significant work:

1. Can the author explain the discrepancy between the date of the implementation of GeneXpert (2017) and the data which include 2015 and 2016

2. Can the author confirm the methodology - here a flow diagram may be useful - outlining the sensitivity and specificity of microscopy as well as the exact staining and review process used

3. This manuscript still requires extensive English language editing

Please submit your revised manuscript by May 19 2023 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.

Please include the following items when submitting your revised manuscript:

• 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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,

Elizabeth S. Mayne, M.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

This manuscript still requires significant work:

1. Can the author explain the discrepancy between the date of the implementation of GeneXpert (2017) and the data which include 2015 and 2016

2. Can the author confirm the methodology - here a flow diagram may be useful - outlining the sensitivity and specificity of microscopy as well as the exact staining and review process used

3. This manuscript still requires extensive English language editing

[Note: HTML markup is below. Please do not edit.]

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 #3: All comments have been addressed

Reviewer #4: (No Response)

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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 #3: Partly

Reviewer #4: No

**********

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

Reviewer #3: I Don't Know

Reviewer #4: I Don't Know

**********

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 #3: No

Reviewer #4: Yes

**********

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 #3: Yes

Reviewer #4: No

**********

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 #3: Data in Table 1 shows an increase in TB testing (Total), I would like to know the reasons for the increase uptake from 4 635 in year 2015 to 17 572 in Year 2018.

Secondly, the method for diagnosing using smear, was it a single smear per participant? if so why do we see an increase in uptake as GeneXpert testing is introduced.

Reviewer #4: - There are serious issues with style and grammar that affect comprehension and require editing

- There is inconsistency between information given in background and results: the background states that GXP was introduced in 2017, yet GXP data is presented from 2015 onwards

- The background lacks information on microscopy and GXP in terms of performance data/limit of detection

- The method section is flawed; there is no information on MTB testing algorithms in the laboratories; no information on which AFB microscopy method was used; no information on treatment regimens for MDR TB; extracted data and analysis thereof is not clearly stated

- The results section doesn't mention proportion of patients on DS or MDR treatment; patients with extra-pulmonary TB are included yet the methods section only mentions sputum samples-- how were these diagnosed and from which samples?; the impact of the GXP introduction on treatment outcomes is not mentioned in results and should be elaborated on; relevance of adding data for various 'sub-cities' not clear unless of local interest

- Comments by previous reviewers have not been adequately addressed

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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.

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 #3: No

Reviewer #4: 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. Please note that Supporting Information files do not need this step.

PONE-D-21-40508R3Impact of GeneXpert on TB Diagnosis and Anti-TB Treatment Outcome at Health Facilities in Addis Ababa, Ethiopia: In the Post MDG YearsPLOS ONE

Dear Dr. Getahun,

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.

All 3 reviewers suggest that there have been substantial improvments to this manuscript although there are a number of grammatical and typographical errors. As suggested, please also include a more focused description as to the link between the introduction of the GeneXpert and the improvement of TB outcomes. Also, please explain why a number of patients included had "clinical" diagnoses and how these were improved by introduction of the Gene Xpert.==============================

Please submit your revised manuscript by Aug 03 2023 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.

Please include the following items when submitting your revised manuscript:

• 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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,

Elizabeth S. Mayne, M.D.

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.

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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 #3: All comments have been addressed

Reviewer #4: (No Response)

Reviewer #5: All comments have been addressed

**********

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 #3: Yes

Reviewer #4: Partly

Reviewer #5: Partly

**********

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

Reviewer #3: Yes

Reviewer #4: I Don't Know

Reviewer #5: Yes

**********

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 #3: Yes

Reviewer #4: Yes

Reviewer #5: Yes

**********

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 #3: Yes

Reviewer #4: No

Reviewer #5: Yes

**********

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 #3: The manuscript has done a thorough analysis of the data and highlighted the important key points in question.

Reviewer #4: Many thanks for addressing some of the previous queries regarding the manuscript.

I would suggest additional work on the following issues

- Style and grammar require further review, there are several phrases and words that are not idiomatic or incorrect. Please also review the tense in which the various sections are written. Some examples highlighted in yellow in attachment.

- Not all abbreviations are explained in the text (see PTBN and PTBP under ‘demographics and clinical characteristics’).

- Should the sentence in the discussion in the third paragraph ‘Male patients who were diagnosed with TB had higher odds of being positive..’ say ‘screened’ rather than ‘diagnosed’? A positive test would lead to the diagnosis, the sentence as it stands doesn’t seem to make sense. This appears again on another occasion in the discussion.

- The discussion still lacks a clear structure and a logical flow, and should focus more on the main aims of the study which were to show a link between increase in Xpert testing and TB diagnosis and treatment outcomes.

The link between introduction of Xpert and improved treatment outcomes is tenous and does not appear to be supported by the data: the treatment outcome group that was analysed appears to include patients that were diagnosed clinically and a large number of patients with extra-pulmonary TB who were also not diagnosed with Xpert it seems (or ?unknown how they are diagnosed). Yet the discussion states that Xpert ‘brought an improvement in…success rate of treatment outcomes’. Please could you clarify how you came to this conclusion? There are recent review articles that have not shown a strong link, ie F Haraka 2021 ‘Impact of the diagnostic test Xpert MTB/RIF on patient outcomes for tuberculosis’ and G Di Tanna 2019 ‘Effect of Xpert MTB/RIF on clinical outcomes in routine care setting: individual patient data meta-analysis’. You do mention in your limitations that other factors that may have had an impact on treatment outcomes were not taken into consideration; I feel this has to be expanded on as it is very relevant. It is mentioned that patients with drug resistant TB were excluded from the analysis so any advantage of picking up rifampicin resistance using the Xpert cartridge on treatment outcomes will not be assessed if I am correct?

Reviewer #5: I think that this is an important subject and provides valuable information on implementation of Gene Xpert, however, there are still a number of errors that need to be addressed for example in the second paragraph of the discussion, they state that there has been a 4 fold increase in identified TB cases, I think the correct term is, confirmed TB cases have increased 4 fold. Similarly, in paragraph 5 of the discussion they state that the cure rate pulmonary TB was 92.9%, they previously should either clarify that they are referring to the PTBP or cite the actual pulmonary TB cure rate which was 27.3%. While the authors have addressed the comments raised by the reviewers there are still some errors that need to be addressed.

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Reviewer #3: No

Reviewer #4: No

Reviewer #5: No

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Attachments

Attachment

Submitted filename: PONE-D-21-40508_R3_reviewer (2).pdf

Impact of the use of GeneXpert on TB diagnosis and anti-TB treatment outcome at health facilities in Addis Ababa, Ethiopia in the post-millennium development years

PONE-D-21-40508R4

Dear Dr. Getahun,

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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Reviewer #4: (No Response)

Reviewer #5: All comments have been addressed

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Reviewer #4: Partly

Reviewer #5: Yes

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Reviewer #4: I Don't Know

Reviewer #5: Yes

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Reviewer #4: Yes

Reviewer #5: Yes

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Reviewer #4: Yes

Reviewer #5: Yes

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6. Review Comments to the Author

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Reviewer #4: Many thanks for the revisions,

I have highlighted in yellow remaining editing that is suggested.

Additional comments:

- References 6-9 in the background do not support the statement that Xpert improves anti-TB treatment outcomes:

No 6 covers test performance criteria, turn-around-time, time to starting treatment

No 7 is a cost-benefit analysis looking at a cohort in a high income/low burden setting

No 8 is a mathematical model

No 9 addresses practical issues with implementation and time to diagnosis

- Please review paragraph in background addressing previous and current use of Xpert in your area and the tense used, how you were testing previously and how you are testing now; it requires clarity

- Operational definitions: add ‘retreatment’ as mentioned in tables

- Elaborate on 3rd point in discussion: other factors and actions to improve outcome

I still have concerns about causality versus observation with regards to Xpert introduction and treatment outcomes. You have described an increase in use of Xpert and observed an improvement in treatment outcomes over this time period which is important to describe. The diagnosis with Xpert is more accurate and sensitive and should enable patients to be diagnosed and started on an efficient regimen earlier. But in my opinion there are many other factors involved in successful treatment outcomes and further research is required to prove causality.

Reviewer #5: The Authors have made adequate changes to the manuscript and based on that I accept the manuscript as is.

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Reviewer #4: No

Reviewer #5: No

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