PONE-D-21-26982

Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)

PLOS ONE

Dear Dr. Lalloo,

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PLOS ONE

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When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

4. Thank you for stating the following in the Acknowledgments Section of your manuscript:

“Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701; clinical trial aidsinfo.nih.gov/clinical-trials/details/NCT00885703. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. FCZ was provided by Pfizer.

We thank the following A5225 researchers and research teams for their contribution to the study: Mohammed Rassool, MBCHB and Noluthando Mwelase, MBCHB- University of the Witwatersrand Helen Joseph (WITS HJH) CRS (11101) CTU Grant AI069463, Dr Rosalina Mnqibisa MBChB, and Dr Mergan Naidoo MBChB, M.Fam.Med, MSc, PhD- Durban International CRS (11201) CTU Grant UM1AI069432, 11302, San Miguel CRS CTU Grant AI069438, Alejandro Sanchez, MD & Hannah Edmondson, RN, MPH- University of Southern California CRS (1201) CTU Grant UM1AI069432 and 5 U01 AI069428, Sandra Rwambuya, MPH and Aggrey Bukuru, MBChB- Joint Clinical Research Centre (JCRC)/Kampala CRS (12401) CTU Grant UM1AI069501, 12501, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS CTU Grant UM1AI108568, Abraham Mosigisi Siika -MBChB, MMed, MS and David Kiplimo Lagat- MBChB, MMed- Moi University Clinical Research Center (MUCRC) CRS (12601) Grant UM1AI10856, 30313, Parirenyatwa CRS CTU Grant UM1AI069521, 31441, Byramjee Jeejeebhoy Government Medical College CRS CTU Grant UM1AI069465, Patcharaphan Sugandhvesa, M.D. and Daralak Tavornprasit, M.Sc. -Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS (31784) Grant Number: 5UM1AI069399-12, John MacRae, MD,  Asociacion Civil Impacta Salud y Educación and  Eduardo Ticona, MD Hospital Nacional Dos de Mayo. Lima, Peru Grant number AI069438

 We express a special note of appreciation to all participants and their families and supporters for participation in this study.”

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

“Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701; clinical trial aidsinfo.nih.gov/clinical-trials/details/NCT00885703. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. FCZ was provided by Pfizer.”

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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: No

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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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: No

Reviewer #3: 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: Yes

Reviewer #2: Yes

Reviewer #3: 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: This is a complex but interesting randomised study which questions the recommendation by WHO to use 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in person living with HIV (PLWH) in settings where amphotericin-B (AMB) is unavailable. The authors conclude that weight-based induction doses of FCZ between 1600mg/day and 2000mg/day are safe, well tolerated and that the higher dose of 1600mg FCZ should be recommended in settings where AMB is not available on the basis of no statistical difference compared to AMB in mortality. In contrast the WHO recommended 1200mg FCZ dose was associated with poorer survival.

I have a number of concerns:

1. The 1200mg FCZ dosage was ruled out by SMC in Stage 1 for lack of efficacy, so there is no randomised comparison between this dosage and the others.

2. The FCZ 1600mg/day and 2000mg/day dosages were weight-adjusted so effectively a proportion of people actually received lower doses (as low as 1000mg/day). What was the proportion of people receiving <1600mg/day and <2000mg/day in the two arms? I recommend a per-protocol analysis also to be conducted.

3. As often happens when conducting a trial across multiple resource limited international sites there are delays in implementation of the protocol and treatment guidelines are likely to change over the duration of the study creating challenges, such as the addition of the AMB arm in 2011. Also Stage-1 and Stage-2 participants have been combined. One possible consequence could be the observed imbalance between the randomised groups in key confounders such as age and weight and CrAG titer as shown in Table 2. In particular people randomised at 1600mg/day were on average 3 years younger and 4 Kg lighter than those randomised to AMB. CrAG titer was much lower in the FCZ arm. These differences could have biased the comparison. I suggest that the results of a Cox regression after controlling for these imbalances is added in the Results.

4. Statistical power is also an issue. 1600mg/day is judged to be non-inferior to AMB although the difference in mortality at 24 weeks was 6% (30% vs 24%) which does not appear negligible. There is evidence that ABM is superior to FCZ 1600mg/day to achieve a negative culture. This seems to be the most important mediator for survival suggesting that the lack of significance (p>0.14) is only the result of lack of statistical power and cannot be interpreted as ‘non-inferiority’.

5. To increase readability the pairwise comparison p-values of FCZ with AMB (shown in table 5, not Table 3 as indicated on page 9) should be added to the KM figures.

Reviewer #2: This is an interesting study assessing higher dose of fluconazole for naive patients with CM. In several LRCs, given the absence of flucytosine and, often, of AMB the results may have significant clinical implications.

Yet I have some comments:

ABSTRACT and THROUGHOUT the STUDY: patient disposition is quite complex and the lack of data on the 1200 mg arm in the results section of the abstract is somehow catching the eye. I am also confused on the complex study history: while it is needed for explaining the long duration and accrual it is not entirely clear to me.

BACKGROUND:

X Maybe citing liposomial AMB could be beneficial dspite its lack in LRCs

X Several guidelines (including NIH) suggest FCZ 800 mg as consolidation phase: maybe a comment on this can be added.

METHODS:

X No mention of the randomization process is included (block? any sratification?)

X Able to take oral medication is a key inclusion criteria but it could have also been a selection bias (is it available the number of participants not included for such reason?)

X 8 patients received rifampicin (active TB? TBM?) did they differ in terms of outcome?

X there is no mention of IRIS cases and associated mortality

X I coulod not find the statement on data availability as for PlosOne policy

RESULTS AND DISCUSSION:

X The impairment in study participants at baseline is, although by chance, a serious problem for understanding the study outcomes. Specifically patients on FCZ 1200 mg had several features associated with worse outcomes. Is it possible to create a multivariate model including treatment arm and baseline features? However acknowledgeing this in the discussion is, in my opinion, important.

X I was not able to find concomitant oportunistic infections according to study arms (since they may affect mortality and HAART initiation)

X CFU decrease according to study arm: are pairwise comparisons significant? FCZ 1200 and FCZ 2000 seem pretty similar in terms of CFU reduction

X Plasma PK data have not being included: are PK studies ongoing? Will they be available?

X Low eGFR is a risk factor for severe comorbidities and worse outcomes: were participants receiving eGFR-adjusted doses at higher risk of worse outcomes and poor antifungal reponse?

X Discussion pag-12: I believe that acknoweldging the potential impact of several other factors on mortality (as suggested in the last lines of page 14) is crucial for having a fair discussion.

Reviewer #3: This paper with title "Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal

Meningitis (HIFLAC)" describes an important piece of research on optimal fluconazole dosing in cryptococcal meningitis.

I congratulate the authors for the work and efforts done to complete this lengthy and laborious trial, which gives important insight on the suboptimal efficacy of what is considered standard of care for Cryptococcal meningitis in resource limited settings (due to unavailability of Ambisome and flucytosine).

I have a number of suggestions /questions to address as minor changes:

The title is concise and appropriate.

1. ABSTRACT - it summarises well the main findings however in the findings part "FINDINGS: 168/154 (safety/efficacy) participants were enrolled with 48/46, 50/45, and 48/43 in the AMB, 1600mg and 2000mg cohorts" I find confusing/unclear how to interpret the results not having read the whole article( eg why more patients were evaluated for safety than efficacy?)

I'd suggest to rephrase or select only to describe efficacy data for instance.

2. In METHODS -

2a The study was approved by the USA Food and Drug Administration and country specific IRBs.-> IRBs needs specification

2b Line "Participants were enrolled in consecutive cohorts at each dose level in Stage-1 and randomized to receive FCZ or AMB in a 3:1 ratio" -> it can be confusing when reading re:consecutive cohorts (as one might think it is the same patient randomised to different doses) - suggest to better clarify what is meant by consecutive cohorts

2c. Line "In Stage-2, participants were concurrently randomized 1:1:1 to receive one of two daily doses (1600mg and 2000mg) of FCZ or AMB". Missing a full stop and would advise substituting “receive one of two daily doses” with “receive either 1600 mg or 2000 mg of fluconazole or AMB” for ease of reading.

2d. Line "In both stages treatment was up to 4 steps followed on study" again unclear, would rephrase

2e. Treatment - Line "Rifampin containing TB treatment was not permitted in the 1200mg FCZ induction cohort. Participants receiving rifampin in the consolidation phase (Step 3 and Step 4) had to take at least 1600mg/day FCZ. There were 4 participants with TB on rifampin in the 1600mg and 2000mg cohort" -> this patients should not be used for the efficacy analysis as fluconazole exposures are significantly reduced by rifampicin co-administration (22% decrease in AUC, 17% decrease in Cmax and 30% higher elimination rate- D panmovana Clin Pharmacokin. 2004 ) - those patients were effectively on lower fluc doses.

2f. Stopping rules - Line "Three or fewer participants with a toxicity event permitted escalation to the next dose; 4-9 instances did not permit escalation, and this would be regarded as the maximum tolerated dose (MTD); more than 9 instances would indicate that the prior dose would be the MTD.” Again I find this difficult to read, unclear. Please rephrase to explain better. What is it mean by instances?

2g. Sample size - the following is difficult to read and unclear, to be clarified/rephrased “This phase 1/2 studywas designed to have 90% power and a one-sided 0.10 alpha test to detect a difference in mean change in log10 CFU/mL CSF/day of about 80% of the standard deviation of the measures in stage-1A sample size of 24 participants in the FCZ arm of each Stage-1 cohort would detect a dose limiting toxicity (DLT) rate > 25% of participants and would provide guidance on efficacy for the choice of cohorts in Stage-2.”

2h. the line “Additionally, with >40 evaluable participants per dose, there is an 87% chance of seeing one or more rare events if the unacceptable event occurs at a rate of 5% or higher”please clarify what is meant by unacceptable event

3. RESULTS

3a I personally found the results section difficult to read, mostly describing what is found/seen in the relative tables and figures however the main findings should be described clearly in the text with reference to tables/figures for the complete findings. I would suggest to work on the result section to improve the description of the findings.

3b Line “Several participants with hyponatremia and hyperkalaemia received a glucocorticosteroid: 9/25 FCZ 1600 mg, 8/23 FCZ 2000mg, and 9/19 AMB" . It would be important to specify what glucocorticoid was given and at what dose, as this could potentially be confounding the results.

FIGURES

Figure 1. following sentence needs checking “Participants from Stage 1 for each of the 1600mg and 2000mg FCZ and AMB cohorts were combined with the participants”

Figure 2. correct the sentence “There was no difference when participants who failed fluconazole and were switched to amphotericin B”

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Margherita Bracchi

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PONE-D-21-26982R1Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)PLOS ONE

Dear Dr. Lalloo,

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. Two of the previous reviewer were available to provide further comments on your study and were happy with your revision. However it was considered necessary to obtain comments from an additional reviewer. The reviewer's comments are available below. The reviewer raised some scientific concerns about the study that need to be addressed in a revision.

Please revise the manuscript to address all the reviewer's comments in a point-by-point response in order to ensure it is meeting the journal's publication criteria. Please note that the revised manuscript will need to undergo further review, we thus cannot at this point anticipate the outcome of the evaluation process.

Please submit your revised manuscript by Dec 02 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:

• 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,

Miquel Vall-llosera Camps

SeniorEditor

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 #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

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

Reviewer #2: I Don't Know

Reviewer #3: I Don't Know

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 #2: Yes

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 #2: Yes

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 #2: Thanks for addressing all my comments. I believe the manuscript is more clear now and all the data have been explained smoothly.

Reviewer #3: Thank you for the revision work performed on the manuscript. All the comments raised and suggestions have been addressed.

Reviewer #4: This study involves a complex study design aiming to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ. Given the less availability of amphotericin-B (AMB) and flucytosine, the results can be impactful.

1) It is claimed the induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated according to the statistical testing criteria defined; however, according to the results, for example, Figures 2,3, & 4, the AMB group seem to be systemically superior, even though the statistical test significance levels didn’t reach the defined criteria. One can argue it’s a power / sample size issue. It seems to me the AMB treatment can be regarded as the gold standard, and an inferior test / equivalence test should have been used.

2) There are typos in the manuscript. For example, in Abstract, “proportin”; in the first paragraph of Introduction, “maybe” should be “may be”.

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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 #2: No

Reviewer #3: Yes: margherita bracchi

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.

Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)

PONE-D-21-26982R2

Dear Dr. Lalloo,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Renee Ridzon

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #2: 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 #2: Yes

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 #2: Yes

Reviewer #3: Yes

Reviewer #4: 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 #2: Thanks for addressing all my comments. I have no other change to require. From my point of view it can be accepted as it is.

Reviewer #3: All queries have been successfully answered in my opinion. I had no additional comments and previously stated that the paper was to be accepted for publication.

Reviewer #4: My comments were addressed. There is no further critique.

My comments were addressed. There is no further critique.

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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 #2: No

Reviewer #3: No

Reviewer #4: No

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