PONE-D-24-02035Persistent Advanced HIV Disease in Rural KwaZulu-Natal, South Africa: Trends, Characteristics, and the Urgent Need for Targeted InterventionsPLOS ONE

Dear Dr. Kitenge,

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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: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: I Don't Know

Reviewer #4: Yes

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

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: No

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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: PONE-D-24-02035

Advanced HIV disease and CD4 in KZN 2008 – 2021

Ther authors report the prevalence and patterns of advanced HIV disease (AHD) at presentation to care between 2008 and 2021 in KwaZulu-Natal, South Africa. In addition, the cohort was followed-up to determine factors associated with CD4 recovery after entry into care with AHD. The proportion of people entering care with AHD decreases as the South African antiretroviral therapy (ART) policies become more inclusive. However, the numbers remain high and in later years, participants with AHD are more likely to be ART-experienced, especially men. CD4 recovery can occur in those who return to and remain in care for some time. This is an important topic as HIV services mature; its sampling of a rural population is a strength.

The paper is well-written but with several typos and missing words (lack of attention to detail). The formatting is all over the place. Line numbering only starts in the Discussion and there are no page numbers which has made the review more difficult.

The statistical tests are appropriate and the limitations are described.

General comments:

Please spell out the abbreviations at first use in the abstract, manuscript and tables.

Major comments.

The description of the study design as cross-sectional is a bit misleading as the cohort is followed-up and the analyses applied appropriately for longitudinal data. It would be more accurate to describe a cohort study and present the prevalence of AHD at entry into care (baseline) which is how the cohort is defined.

The description of table 1 is unclear and disorganized. Specify MEDIAN CD4 count. At one point MEAN is presented (S1) but MEDIAN has been used elsewhere. Where are the data on median/mean CD4 presented? In Table S1 why are the means presented when medians are reported in the text? I assume there is a difference between TIME ON ART and FOLLOW-UP TIME in the study. These are confused.

Throughout the analyses when age is used as a categorical variables and 18-24 years is the reference, only data for the 25–31 year category are presented when the effect on the OR/aOR is in the same direction for ALL age categories. it is not clear why 25-31 has been chosen. It could be presented as >24 years.

In all the Tables, please label how the data are presented in the table. E.g., n (%) or median (IQR) etc.

Table 3: I don’t understand the Males/Females with first CD4 test columns.

Line 1: is the CD4 recovery on the ART-naïve or ART-experienced group or both?

Line 6: TB at ART start or TB ever?

The Discussion is overly long and can be condensed. E.g., description of Universal Test and Treat policy; Implications and Future research para 2 repeats para 1

Minor comments

Background, third line: million is duplicated – both the figure and the word are used.

Background further down: ¾ - can’t be right; stage 3 or stage 4

Definitions and outcomes, 3rd sentence: and who experienced a drop…

Statistical analysis, near the end: death and LTFU are competing risks, plural (not a competing risk, singular).

Results, 2nd line: specify/describe the universal test and treat policy. Do not assume the reader is familiar with South African policy. The DATE/S need to be included.

Burden and trends of AHD among ART-experienced patients, line 4: the subject is missing from the sentence. What increased from 4% to 63%?

Before the Table 2 heading there is an incomplete sentence in bold. Why bold? Need to complete sentence.

Line 91: no subject. I think you mean selection bias

References:

Include the url and Access Date for on-line sources

Reviewer #2: The study addresses an important public health issue in a setting with high HIV prevalence. It is well written and the team is commended for that. The folowing are my comments and suggestions

1. In the methods section, why did the authors choose Eshowe and Mbongolwane specifically, beyond HIV rates which are high in the whole of KwaZulu Natal?

2. Justify the use of and assumptions for the mixed effect regression and Poisson models

3. The last sentence here is incomplete: Factors associated with AHD among ART-naïve patients.

In the mixed-effect logistic regression, being male (aOR 1.80; 95% CI 1.71 to 1.90), PLWH

aged 25-31 years (aOR1.65; 95% CI 1.52-1.79) and having TB (AOR 2.46; 95% CI 2.19-2.76)

had higher odds of AHD at ART start (

4. The pages are not numbered

5. Resolve formating issues on multiple pages that are distracting when reading an otherwise well written manuscript

6. The statement: "Finally, having started ART between 2012 and 2015 (aSHR 0.60; 95% CI 0.56 to 0.65) or between 2016 and 2021 (aSHR 0.54; 95% CI 0.49-0.59) compared to having started ART between 2008 and

2011" is incomplete.

7. It would be useful to provide a statistic in place of the words "consistently high" in the opening statement of the discussion.

8. In your discussion of implications for the study, you mention only differentiated care models, but other options are available and may be worth mentioning, such as community support programs, digital adherence tools and so on. There is a need to broaden the options to solve this problem.

Reviewer #3: Background section

Paragraph 1

• Reference 1 does not contain the quoted stats. It might be better to use the WHO country data:

o https://www.who.int/data/gho/data/indicators/indicator-details/GHO/reported-number-of-people-receiving-antiretroviral-therapy

5 588 062 people in SA on ART in 2021

o https://www.who.int/data/gho/data/indicators/indicator-details/GHO/estimated-antiretroviral-therapy-coverage-among-people-living-with-hiv-(-)

75% ART coverage in SA in 2022

• The “Treat all policy” was known as the “Universal Test and Treat policy” in South Africa (2016); it is available at:

http://www.kznhealth.gov.za/test_treat.htm

https://sahivsoc.org/Files/PREP%20and%20TT%20Policy%20-%20Final%20Draft%20-%205%20May%202016%20(HIV%20news).pdf

https://sahivsoc.org/Files/22%208%2016%20Circular%20UTT%20%20%20Decongestion%20CCMT%20Directorate.pdf

These might be better references for implementation of UTT policy in SA.

Background, Paragraph 2

• WHO ¾ stage should be re-written as WHO stage 3 or 4

Setting and participants section

• “…of which only 1.1 million are receiving…”, should be re-phrased as “…1.1 million of whom are receiving…”

• Eshowe and Mbongolwane are mentioned under study setting, but not rationale is given as to why these populations were chosen for the study. Especially if you are drawing conclusion on AHD in rural areas, an attempt should be made to describe the rurality of the setting, and the generalizability to other rural settings.

• No context is given on the relationship between umlalazi municipality (mentioned in the Data Sources section) and Eshowe and Mbongolwane.

Statistical analysis Section

• The use of the Fine-Gray competing risks regression with a proportional sub-distribution hazard (SHR) model should perhaps be references as some readers may be unfamiliar with the method.

Results section, paragraph In the multivariable competing risk regression model of time to CD4 recovery >350 cells/μL following a CD4 <200 cells/μL adjusted for clustering at the health facility, lines 1 to 10.

“These factors were associated with a reduced risk of CD4 recovery to >350 cells/μL.” It is unclear what factors you are referring to, as all above-mentioned factors has a better CD4 > 350 recovery.

There was also a better CD4 > 350 recovery on non-stavudine containing regimens, which is not mentioned here.

Table 1:

• “Stavudine” is misspelled

• “ART start” should be changed to “ART initiation” for consistency of terminology.

Discussion Section, line 12 to 19

• The description of AHD in the rural setting, should be contrasted with the existing literature about urban settings.

Discussion Section, line 30

• “September 2015” should be corrected to “2016”.

The SA DoH guideline of 2015 set the CD4 threshold at 500, available here:

https://sahivsoc.org/Files/ART%20Guidelines%2015052015.pdf

• The other factors besides gender, which affect CD4 recovery i.e. age group, ART regimen, time period in which ART was initiated, being on TB treatment – also warrant further discussion.

Figure 2

Suggestion: Add overlying labels on the figure, showing the changes in national policy on CD4 threshold at ART initiation. The decline in AHD does follow the policy changes from CD4 of 200 in 2008, to 350 in 2013, to 500 in 2014, then to UTT in 2016.

Sahivsoc.org has the old DOH policies, if you are looking for them.

S1 Appendix.

• The title: Predicted average relative risk of Males with First CD4 count <200 cells/mL

by age group. Does not match the info on the graph.

The y-axis on the graph should specify whether that is the CD4 at initiation or whether it is the change in CD4.

S2 appendix and S3 appendix

• It is unclear what is being demonstrated here. Perhaps these percentages should be accompanied by absolute numbers. Or another analysis should be done - % of people on ART with no interruption, and VL <1000 with a CD4<200, over time.

This will tell you whether there is a truly increasing burden of failure of immune recovery while on effective ART, (which I highly doubt there was)

The data is the current format don’t give that information, as there was an increasing number of people on ART over time. So the proportion in that category will logically increase over time.

Reviewer #4: Thank you for the opportunity to review this manuscript on advanced HIV disease in a rural population in KZN. The manuscript describes an important topic around which renewed focus is needed, and these are valuable data to add to the evidence body.

The presentation and readability of the results section of the manuscript could be improved.

A few more specific comments below

Background

Amend “WHO ¾ stage” to read “WHO stage 3 / 4” or “3 or 4”

Methods

Your inclusion criteria state “Our study included all individuals

aged 18 years and older living with HIV who were receiving ART, and who had undergone

baseline and subsequent CD4 cell measurements between January 2008 and June 2021.”

Please define what baseline is in this case.

Although it is mentioned in the limitations of the study, it would be useful to include in the results (in Figure 1) the numbers of adults on ART who were excluded because they did not have a CD4 cell count at ART initiation and the numbers without a subsequent CD4 measure. With the introduction of treat all CD4 testing has declined, and this could introduce bias into the results, since those who receive CD4 testing are sicker. It would help the reader assess the potential for bias in your results.

Last sentence under ‘Data sources and variable’ is missing a word.

Results

The title for Figure S1 is incorrect

Table 3 may be better presented as a graph

Second last sentence of results is incomplete: “Finally, having started ART between 2012 and 2015 (aSHR 0.60; 95% CI 0.56 to 0.65) or between 2016 and 2021 (aSHR 0.54; 95% CI 0.49-0.59) compared to having started ART between 2008 and 2011.”

It may be better to summarize the factors associated with reduced risk of CD4 recovery without providing the aSHRs in the text, to improve readability.

Please clarify what prior attendance unknown means?

Results show later year of ART start reduced risk of AHD on ART, could this be as a result of less follow-up time? Would be worth adding to the discussion about this result

Discussion

More discussion about the ART-experienced patients with AHD would be beneficial. From your Figure S2 it looks like an increasing proportion are in care (ART experienced, regular attendance) and not treatment interrupters, and the majority (69%) were virally suppressed. Some further clarity on these results is needed in the discussion.

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Reviewer #1: No

Reviewer #2: Yes:  Gershom Chongwe

Reviewer #3: Yes:  Kerusha Govender

Reviewer #4: No

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Attachment

Submitted filename: PONE-D-24-02035.docx

PONE-D-24-02035R1

Persistent Advanced HIV Disease in Rural KwaZulu-Natal, South Africa: Trends, Characteristics, and the Urgent Need for Targeted Interventions

PLOS ONE

Dear Dr.  Kitenge,

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.

I want to congratulate you all for trying to respond to the editor/peer reviewers’ comments and suggestions. This is a n excellent finding of that could be an input for province/national HIV policy. Yet, there are some remaining constructive suggestions: - pay attention to reducing the size of the article through summarizing and trimming sections; and sticking to PLOSE ONE journal structure/requirement.

Please submit your revised manuscript by Nov 18 2024 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,

Zewdu Gashu Dememew, 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.

Additional Editor Comments:

Dear Authors,

I want to congratulate you all for trying to respond to the editor/peer reviewers’ comments and suggestions. This is a n excellent finding of that could be an input for province/national HIV policy.

Yet, there are some remaining constructive suggestions: - pay attention to reducing the size of the article through summarizing and trimming sections; and sticking to PLOSE ONE journal structure/requirement.

Best,

[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 #1: All comments have been addressed

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 #1: Yes

Reviewer #3: Yes

Reviewer #4: Partly

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

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: 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: No

Reviewer #3: Yes

Reviewer #4: No

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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

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 #1: Thank you for the revised manuscript. My comments have been adequately addressed.

The formatting is still problematic but I assume this will be sorted out during production.

Line 62: men living with HIV

Line 63: typo HIB = HIV

Supporting Information 1st graph: heading includes CD41

Reviewer #3: All reviewer comments have been sufficiently addressed.

I have no additional comments

Reviewer #4: Many thanks for the opportunity to re-review this manuscript. I recommend that this manuscript undergo further editing to improve readability.

Below are my further comments:

• I agree with the other reviewers regarding their suggestions for the age groupings used in this analysis. The authors response does not appear to justify their choice of age-groupings either. They reference their choice as being based on the international journal of epidemiology guidelines which are: “age grouping should be mid-decade to mid-decade or in five-year age groups (e.g. 35-44 or 35-39, 40—44, etc, but not 20-29, 30-39 or other groupings).” The authors have chosen 7-year age bands (25-31, 32-38, 39-45) which are not in line with this recommendation. I recommend amending the analysis to be in line with these guidelines.

• Based on my recommendation the authors added the definition of prior attendance unknown to the methods section: “We also defined prior attendance unknown if the patients had neither a ≥90-day interruption in care nor regular attendance or continuously in care.” I feel this sentence can be clarified further. It implies that “regular attendance” is different from “continuously in care”, and neither of these terms have been defined. I feel the authors should explicitly state that they had a variable for patient attendance and state and define each of the 3 categories.

• Results section where the factors associated with AHD among ART-naïve patients are described could be further edited for clarity and readability

• Suggest rephrasing the term “during ART” to “after ART initiation”, since it includes PLWH who interrupt treatment.

• If I understand correctly the AHD among ART-experienced group includes only patients who initiated ART with a CD4>200. The results which describe these patients seem to suggest that the majority (58%) were continuously in care, and virally suppressed (69%).

o In the discussion it is stated: “there was an increase in the number of PLWH with AHD who were ART-experienced (PLWH who have previously initiated ART and are re-engaging with AHD after a period without effective ART or failed therapy).” This definition in parenthesis does not agree with what was described in the results (that the majority were continuously in care, and virally suppressed) nor does it match the definition that was stated in the methods section: “ART-experienced patients were those who entered care with CD4 count ≥ 200 cells/μL and who experienced a drop in CD4 count to <200 cells/μL during follow-up (exposure to ART for at least 6 months or more), including those lost to follow-up and who returned to care.” I suggest removing the definition in brackets from the discussion.

o I also suggest removing the sentence: “Of these AHD patients who were ART-experienced, 27% had either had a prior attendance unknown or interrupted treatment for 90 days or more and 14% had a detectable VL of ≥ 1000 copies/ml, suggesting either adherence problems or failed therapy.”

o I suggest adding to the subsequent sentence: “Additionally, among those ART-experienced patients with AHD with documented VL, 69% were virally suppressed.”, that 58% were continuously in care.

o The authors correctly include a discussion about AHD and cycling in and out of care as there is much literature to support this. But your results do not agree with this statement. The authors also say “These findings underscore the necessity for strategies aimed at closing gaps in HIV care, promoting re-engagement interventions (48), and encouraging individuals to return before experiencing significant deterioration (49, 50).” I agree with these sentiments, but the study’s results do not show this since the majority of those with AHD after ART initiation were continuously in care and virally suppressed. While the authors have now included a sentence about patients who experience AHD despite ART and VL suppression, the rest of the paragraph needs to be reframed to be in line with the results. The authors reference the ZIMPHIA survey, but in that study only 30% of patients with advanced disease were virally suppressed. The authors have not discussed the much higher proportion of 69% that was found in this study or possible reasons for this.

o Reference 44 and 45 which are meant to support the statement do not seem to be appropriate: “The subset of PLWH experiencing AHD despite prolonged ART and viral load suppression has been noted in several other studies from the region (43-45).” The Ousley study is of hospitalized patients and found that between 81% and 84% of patients admitted to hospital who were ART experienced also had a detectable VL of >1000 copies/mL. This study’s findings seem to be exactly opposite to the point the authors are trying to make. The Nanzigu study (ref 45) describes immune recovery and offers no evidence about advanced disease and viral suppression.

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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 #1: No

Reviewer #3: Yes:  Kerusha Govender

Reviewer #4: No

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[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.

Attachments

Attachment

Submitted filename: editor comment _kuwazulu.docx

Persistent Advanced HIV Disease in Rural KwaZulu-Natal, South Africa: Trends, Characteristics, and the Urgent Need for Targeted Interventions

PONE-D-24-02035R2

Dear Dr. Kitenge,

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

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Matthew J. Mimiaga, ScD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I have facilitated the peer-review of your manuscript, “Persistent Advanced HIV Disease in Rural KwaZulu-Natal, South Africa: Trends, Characteristics, and the Urgent Need for Targeted Interventions.” Overall, the reviewers were enthusiastic about this well-conducted study on trends in annual CD4 count distribution and to characterize adult persons living with HIV (PLWH) on ART who have AHD in rural KwaZulu-Natal, South Africa. All three reviewers found your paper to be of great public health significance and were enthusiastic about its publication in PLOS One. Based on their expert reviews, I am in agreement.

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

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 #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: 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: (No Response)

Reviewer #3: Yes

Reviewer #4: No

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

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Reviewer #1: No

Reviewer #3: Yes

Reviewer #4: 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: (No Response)

Reviewer #3: All comments have been addresssed.

The manuscript is well-presented, and the research has significant implications.

Reviewer #4: Thanks for the opportunity to give input into this manuscript again. I think my comments following the first revision to this manuscript were not seen by the authors as there is no response to these recorded so I have included those that still need to be addressed below:

• I agree with the other reviewers regarding their suggestions for the age groupings used in this analysis. The authors response does not appear to justify their choice of age-groupings either. They reference their choice as being based on the international journal of epidemiology guidelines which are: “age grouping should be mid-decade to mid-decade or in five-year age groups (e.g. 35-44 or 35-39, 40—44, etc, but not 20-29, 30-39 or other groupings).” The authors have chosen 7-year age bands (25-31, 32-38, 39-45) which are not in line with this recommendation. I recommend amending the analysis to be in line with these guidelines.

• Based on my recommendation the authors added the definition of prior attendance unknown to the methods section: “We also defined prior attendance unknown if the patients had neither a ≥90-day interruption in care nor regular attendance or continuously in care.”I feel this sentence can be clarified further. It implies that “regular attendance” is different from “continuously in care”, and neither of these terms have been defined. I feel the authors should explicitly state that they had a variable for patient attendance and state and define each of the 3 categories.

• Results section – Line 163-164 – clearly state or clarify that CD4 at ART initiation rose during the period and not all CD4 counts

• Results section where the factors associated with AHD among ART-naïve patients are described could be further edited for clarity and readability

o Line 168-170 – could be reduced to “being male, those with older age, and those with tuberculosis”, with aORs listed in brackets for each. It is not clear why the aOR for the >45 age group is omitted and all other age groups mentioned

• Suggest rephrasing the term “during ART” to “after ART initiation”, since it includes PLWH who interrupt treatment.

• If I understand correctly the AHD among ART-experienced group includes only patients who initiated ART with a CD4>200. The results which describe these patients seem to suggest that the majority (58%) were continuously in care, and virally suppressed (69%).

o In the discussion (line 57-59) it is stated: “there was an increase in the number of PLWH with AHD who were ART-experienced (PLWH who have previously initiated ART and are re-engaging with AHD after a period without effective ART or failed therapy).” This definition in parenthesis does not agree with what was described in the results (that the majority were continuously in care, and virally suppressed) nor does it match the definition that was stated in the methods section: “ART-experienced patients were those who entered care with CD4 count ≥ 200 cells/μL and who experienced a drop in CD4 count to <200 cells/μL during follow-up (exposure to ART for at least 6 months or more), including those lost to follow-up and who returned to care.” I suggest removing the definition in brackets from the discussion.

o I also suggest removing the sentence (line 60-62): “Of these AHD patients who were ART-experienced, 27% had either had a prior attendance unknown or interrupted treatment for 90 days or more and 14% had a detectable VL of ≥ 1000 copies/ml, suggesting either adherence problems or failed therapy.”

o I suggest adding to the subsequent sentence: “Additionally, among those ART-experienced patients with AHD with documented VL, 69% were virally suppressed.”, that 58% were continuously in care.

o The authors correctly include a discussion about AHD and cycling in and out of care as there is much literature to support this. But your results do not agree with this statement. The authors also say (line 77-79) “These findings underscore the necessity for strategies aimed at closing gaps in HIV care, promoting re-engagement interventions (48), and encouraging individuals to return before experiencing significant deterioration (49, 50).” I agree with these sentiments, but the study’s results do not show this since the majority of those with AHD after ART initiation were continuously in care and virally suppressed. While the authors have now included a sentence about patients who experience AHD despite ART and VL suppression, the rest of the paragraph needs to be reframed to be in line with the results. The authors reference the ZIMPHIA survey, but in that study only 30% of patients with advanced disease were virally suppressed. The authors have not discussed the much higher proportion of 69% that was found in this study or possible reasons for this.

o Reference 44 and 45 which are meant to support the statement do not seem to be appropriate (line 67-68): “The subset of PLWH experiencing AHD despite prolonged ART and viral load suppression has been noted in several other studies from the region (43-45).” The Ousley study is of hospitalized patients and found that between 81% and 84% of patients admitted to hospital who were ART experienced also had a detectable VL of >1000 copies/mL. This study’s findings seem to be exactly opposite to the point the authors are trying to make. The Nanzigu study (ref 45) describes immune recovery and offers no evidence about advanced disease and viral suppression.

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Reviewer #1: No

Reviewer #3: Yes:  Kerusha Govender

Reviewer #4: No

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