PONE-D-21-12722

Associations between plasma nucleoside reverse transcriptase inhibitors concentrations and cognitive function in people with HIV

PLOS ONE

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PLOS ONE

Additional Editor Comments:

This is an interesting study reporting plasma NRTI concentrations and neurocognitiove performance in PLWH from the POPPY cohort.

The reviewers commented on the lack of CSF concentrations and on the need for including TAF for novelty: despite I agree with them (although CSF/brain tissue PK correlation seems pretty poor), both are out of the Journal aims.

I believe the manuscript is valuable and it may improved through some of the changes they proposed (those that are feasable) and by acknowledging the missing data.

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"This work was supported by British HIV Association (BHIVA) research grant. The POPPY study is funded from investigator initiated grants from BMS, Gilead Sciences, Janssen, MSD and ViiV Healthcare (EudraCT Number: 2012-003581-40; Sponsor Protocol Number: CRO1992). The research is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the department of Health."

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: PONE-D-21-12722 attempted to evaluate potential associations between NRTI concentrations and cognitive functions in PWH and showed no associations between certain NRTIs, but some with 3TC. In general, the MS was well written with sound background information, statistical analysis, results and discussion. However, the concentration analyses lack two key components in general: no CSF samples or active metabolites measured. The CSF samples, although remain a surrogate, might be more directly associated with CNS effects, e.g., cognitive function, using some newer references, such as "Switching to Tenofovir Alafenamide in Elvitegravir-Based Regimens: Pharmacokinetics and Antiviral Activity in Cerebrospinal Fluid". NRTIs are well known for their active metabolites and parent drug concentrations in plasma are poorly associated with biological effects. The authors should at least discuss these pitfalls more as part of limitations.

Minor:

The authors should also briefly discuss the NRTI sparing regimens and their potential impact on cognitive function in related to their findings presented in this MS.

Reviewer #2: To the Authors

1. Methods: “PWH were recruited in the POPPY study from HIV outpatient clinics in UK/Ireland from April 2013-January 2016”. What is happened thereafter? As one of the main limitation of the present study, no data from PWH on TAF were provided. The Authors acknowledged that “tenofovir alafenamide was not in widespread use in the UK at the time of study visit”. But, as matter of fact, 5 years have passed from the recruitment of patients. The inclusion of patients on TAF could add great value and novelty to the present investigation.

2. More information should be given on the methods used for the estimation of the AUC in the Methods section.

3. In the Discussion the Authors acknowledged, as potential study limitation, that they were not able to assess the concentrations of NRTIs in the CNS. This is, in my mind, a key information that cannot be missed. To strengthen the value of their findings, the Authors should provide data on CNS concentrations of NRTIs, at least in a cohort of patients, and try to correlate them with cognitive function.

4. As one of the main study findings, the Authors reported that higher plasma 3TC exposures were generally associated with better cognitive performance although higher peak concentrations were associated with poorer performance. In the Discussion the Authors should try to face with the clinical implications of these apparently inconsistent findings.

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Reviewer #1: Yes: Qing Ma

Reviewer #2: No

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Associations between plasma nucleoside reverse transcriptase inhibitors concentrations and cognitive function in people with HIV

PONE-D-21-12722R1

Dear Dr. De Francesco,

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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Kind regards,

Andrea Calcagno

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

I think the authors addressed all reviewers' comments that they were able to (CSF samples were not available).

I believe the manuscript may now be accepted as it is.

Reviewers' comments: