PONE-D-24-40617Quality of life and retention in care among people living with HIV initiated on ART in the era of “Universal Test and Treat” policy at a large HIV Clinic in South Western Uganda.PLOS ONE

Dear Dr. Izudi,

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.

Please submit your revised manuscript by  Apr 24 2025 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,

Professor Kwasi Torpey, MD PhD MPH

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We are unable to open your Supporting Information file S1 File.dta. Please kindly revise as necessary and re-upload.

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

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

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

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

**********

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: Yes

Reviewer #2: Yes

**********

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: Strengths

● Setting of the study is relevant as it is in an area with high HIV burden in Africa so the results are generalizable

● They used a validated tool to measure QoL

● Good description of statistical analysis

● Sample size calculations well described

Weaknesses

● Wording in the abstract and part of the manuscript is contradictory- looking at the results on line 36 contradicts the findings on line 41

● The stratification of CD4 count into only <500 and ≥500 cells/μl oversimplifies the immunological response spectrum. It would have been more robust if there were finer CD4 categorization.

● With universal test and start the usefulness of the study is in question

● Only 81 (27%) of the participants responded to the mental health QoL domain with 277 responding to the physical health QoL however the authors did not explain the reason for the variance calling into question selection bias and the validity of the results

● The definition of retention (active in care ≤7 days after appointment vs. lost to follow-up >7 days after appointment) is quite strict compared to what we would have expected them to use e.g., WHO, definitions (often 30-90 days). The authors should justify this definition and discuss how it might affect comparability with other studies.

● The authors conclude that PLWH with higher baseline CD4 counts have lower mental health-related QoL, but the adjusted odds ratio of 0.56 (95% CI 0.32-0.97) has a confidence interval that nearly includes 1, suggesting a relatively weak association. This should be acknowledged in the discussion. This could be attributed to the sample size

● In lines 268-269, the authors report that the study findings concur with previous reports of , “ significant decrease in mental disorders among PLWH and but mild to moderate cognitive impairment remains high at all stages of HIV infection “ the results presented do not support this conclusion as the MH QoL does not specify what was assessed and the outcomes of the assessments.

● Authors should use more graphs and tables to describe/discuss the results

● While the study adjusted for several variables, other critical confounders such as ART adherence, duration on ART, ART regimen type, and socioeconomic factors were not included in the model.

● Language

○ Some sentences are excessively long, making comprehension difficult.

○ Terms such as "CD4 count at ART initiation" and "baseline CD4 count" are used interchangeably. They should standardize the language

○ The discussion section reiterates findings without substantial analysis

○ There are occasional grammatical errors and awkward phrasings that could be improved.. Generally more proof reading is needed

Minor concerns

● In Table 1, there are some discrepancies in the total numbers for variables like WHO clinical stage (n=275) and most recent CD4 count (n=272) compared to the total sample (n=300). These missing data should be explained.

● Looking at the table some numbers do not add up, WHO clinical stage 3 for example

● The authors report mean physical and mental health-related QoL scores in Table 2, but it's unclear how these scores should be interpreted (e.g., what is the possible range, what constitutes a clinically significant difference).

Suggestions

1. Provide a thorough explanation for the low response rate on the mental health-related QoL domain and discuss the implications for the validity of the findings.

2. Analyze and report the association between time since ART initiation and QoL outcomes.

3. Include a more detailed description of the MOS-HIV tool, including the range of possible scores and what constitutes a clinically meaningful difference.

4. Include data /scores of the different domains assessed using the QoL tool and assess explore associations between CD4 accounts and the different domains

5. Address potential selection bias, as those retained in care until the interview period might have different characteristics than those lost to follow-up.

6. Consider conducting sensitivity analyses with different definitions of retention to assess the robustness of the findings.

7. Discuss the implications of the findings more thoroughly, particularly how mental health interventions might be integrated into HIV care programs for those initiating ART at higher CD4 counts.

Reviewer #2: 1. The manuscript is generally well-organized, with a clear structure and logical progression. The introduction provides a solid background, the methods are detailed, and the discussion contextualizes the findings. However, there are some concerns about the robustness of the data analysis and the conclusions drawn:

a. The manuscript introduction provides a good background but lacks a clear research gap statement.

b. The historical progression of HIV treatment guidelines is informative but too detailed given HIV has been with us for decades and some of it could be summarized in a table.

c. The topic is relevant, though similar studies have been conducted in other settings. The manuscript would benefit from emphasizing how this study adds new insights beyond existing literature.

d. The justification for using the specific QoL measurement tool (MOS-HIV) should be strengthened given there are a number of tools, so important to justify why this specific tool was utilized.

e. The methods section is concise but could explicitly mention sample size justification. It is not clear how the 300 sample size was arrived at. Were all clients enrolled in the two years enrolled or only those with baseline CD4?

f. From the results and discussion, the primary finding, that higher CD4 count at ART initiation is associated with lower mental health-related QoL, is not fully explored. The authors speculate that this is due to ART-related side effects, but no direct evidence such as qualitative interviews or neuropsychiatric assessments is provided to support the claim.

g. Retention in care is analyzed, but the sample size is relatively small (n=300), compared to the clients in the clinic and retention is assessed over a relatively short period. A longer follow up period would give more reliable conclusions. Further, would be good to look at different time periods like 3, 6, 12 ,24 months retention.

h. There is no significant difference in physical health-related QoL or retention, but the authors still discuss the need for interventions to improve retention. While this is relevant, the justification based on the data provided is weak.

i. The categorization of CD4 count as <500 vs. ≥500 cells/µl used in the study is somewhat arbitrary. The manuscript references cut offs of 200, and 350 yet settles on 500 without a specific explanation why the 500 cut off. Especially given that quality of life at the different CD4 cut offs has been shown to be different including risk of those below 200 having high risk of advanced HIV disease compared to those above, sensitivity analyses using different cutoffs (e.g., <200 vs. ≥200, <350 vs. ≥350 ) could strengthen the findings.

j. The results section is repetitive—avoid re-explaining numbers already presented in tables.

k. The authors should discuss alternative explanations for their findings, particularly regarding mental health-related QoL.

l. There seems to be aspects of overinterpretation of results e.g the mental health QoL findings are interesting but should be cautious in attribution. The conclusion that higher CD4 count at ART initiation leads to lower mental health-related QoL is not fully supported by the data. Other attributes such as socioeconomic factors, mental health comorbidities, or ART side effects should be considered.

m. The conclusions in the manuscript align with the results, be more direct and linked to the study’s aims and findings.

n. There’s need to have the policy implications brought out clearly and recommendations for healthcare interventions based on findings. The authors discuss mental health interventions for early ART initiators, but specific recommendations are missing.

o. No mention of study limitations yet important to understand if any potential biases.

2. The authors have done a good analysis and used appropriate statistical models (logistic regression for QoL outcomes and Cox proportional hazards for retention). However, there are some concerns:

a. The assumptions for the Cox model (proportional hazards) are not explicitly tested. The authors should test proportional hazards assumptions for the Cox model.

b. The logistic regression model does not report any goodness-of-fit tests. This is necessary to confirm that the model is valid.

c. The statistical analyses are generally appropriate, but consider analyzing retention further with additional sensitivity checks e.g., competing risks analysis for mortality among those with very low CD4 counts vs. loss to follow-up especially those with high CD4s with the perception of “being well”.

d. The categorization of CD4 count into two groups only groups loses potentially valuable data. Will be better if considered e.g., quartiles or a continuous variable to give reveal additional trends.

e. The study uses a cross-sectional QoL assessment, but the authors attempt to infer causality (suggesting that higher CD4 at initiation leads to lower mental QoL). A longitudinal design would be more appropriate for such conclusions.

f. Tables should be simplified with clear footnotes explaining abbreviations.

g. If possible, analyze QoL differences by gender, age group, or socioeconomic factors to add depth to findings.

3. The manuscript states that all relevant data are fully available. A data availability statement is included, and the data seem to be within the manuscript and supporting files. However, The authors should consider depositing their dataset in a public repository with a DOI for transparency.

4. The manuscript is generally well-written in standard English, but there are some grammatical errors, phrasing that can be improved and redundancies that need to be addressed.

a. Typographical errors noted in a number of areas. E.g lines 51-52: “Globally, there were 39 million people were living with human immunodeficiency virus (PLWH) by the end of 2022 [1].” Has a “were.” Highlighted that is unnecessary

Lines 53-54: “HIV is a treatable and preventable condition with life-long antiretroviral therapy (ART) and its scale-up has led to HIV becoming a manageable chronic health condition, enabling PLWH to live longer and healthier lives, almost comparable to people without HIV.”

The part of sentence “its scale-up has led to HIV becoming…” is off as it makes the sentence read like HIV scale up yet I believe reference is to ART thus could read better as “HIV is a treatable and preventable condition with lifelong antiretroviral therapy (ART). Its widespread use has transformed HIV into a manageable chronic condition, allowing PLWH to live longer and healthier lives, similar to those without HIV.” Line 282-283:

“A study in South Africa revealed that factors such as age, sex, ART, and pill burden reduce the QoL [24].” To note is, “ART” is not a factor that reduces QoL; it should specify “ART-related side effects.”

b. Some sentences are overly complex, making the manuscript harder to follow. For example, lines 69-72 “Early ART initiation (regardless of immune and clinical status) has several clinical and public health benefits such as preventing the progression of HIV to AIDS and preventing its transmission to other individuals as PLWH with undetectable viral load do not transmit HIV dubbed as Undetectable = Untransmittable or U=U [3, 7, 8].” Is too long with lots of information in one sentence, the phrase dubbed doesn’t sound good for a manuscript, and the “Undetectable = Untransmittable” (U=U) concept needs clearer introduction. Consider breaking it for example to read as “Early ART initiation, regardless of immune and clinical status, has multiple benefits. It helps prevent the progression of HIV to AIDS and reduces transmission. Research shows that PLWH with an undetectable viral load cannot transmit HIV, a concept known as ‘Undetectable = Untransmittable’ (U=U) [3,7,8].”

c. Generally, edit as you simplify the long/complex sentences to improve readability.

d. The results section repeats information that is already provided in tables, leading to redundancy. Consider having information in tables not repeated again in the narrative unless giving further details on the results. Instead of repeating full results, focus on key statistical takeaways.

e. Some references are outdated and should be replaced with recent studies (e.g., WHO 2024 guidelines).

**********

6. 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 #2: 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.

Quality of life and retention in care among people living with HIV initiated on ART in the era of “Universal Test and Treat” policy at a large HIV Clinic in South Western Uganda.

PONE-D-24-40617R1

Dear Dr. Izudi

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Professor Kwasi Torpey, MD PhD MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The comments to the authors have been adequately addressed. Where there are differences in opinion with reviewer comments, the explanation provided is satisfactory and reasonable

Reviewers' comments: