PONE-D-20-31760

HIV-1 Gag gene mutations, treatment response and drug resistance to Protease inhibitors: A systematic review and meta-analysis protocol

PLOS ONE

Dear Dr. NKA,

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 apologize for long delay in receiving reviews for your protocol. We have received 3 expert reviews at this time. As you can see, one asks for major revision (reviewer #1), while the other two reviewers have less concern and recommend minor revision of the protocol. I think reviewer #1 did not buy in to the registered report protocol format, so I am placing more weight on the comments of reviewer #2 and reviewer #3. Please do your best to respond to all three reviewers, and modify where it makes sense according to the suggestions. I think we can promise a more swift turnaround for the revised version.

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Paul Spearman

Academic Editor

PLOS ONE

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Additional Editor Comments:

Dear Dr. Durand:

I apologize for long delay in receiving reviews for your protocol. We have received 3 expert reviews at this time. As you can see, one asks for major revision (reviewer #1), while the other two reviewers have less concern and recommend minor revision of the protocol. I think reviewer #1 did not buy in to the registered report protocol format, so I am placing more weight on the comments of reviewer #2 and reviewer #3. Please do your best to respond to all three reviewers, and modify where it makes sense according to the suggestions. I think we can promise a more swift turnaround for the revised version.

Paul Spearman

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

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(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: It is not clear what the aim of the protocol is for. The lack of a purpose of the study also makes it confusing to what unique purpose the review will serve given that there are already existing reviews looking at Gag mutations towards PI resistance, The biggest problem and lack is actually that there is lack of Gag mutations being mapped to specific PI resistance and the corresponding mutations in protease for compensatory mechanism.

The above needs to be addressed for a proper review.

Minor are typos in line 45, 125, 131 where words are just stuck together.

The Background or introduction should state clearly the point of the outcome of the work.

Some suggested points would be to investigate the mechanisms of the mutations.

Reviewer #2: The role of gag mutations/polymorphisms in resistance to PIs is still not clearly understood. This protocol outlines how the authors plan to investigate this by performing a meta-analysis on data (drug resistance, virological failure, subtypes) obtained from published papers and accessible databases on patients failing PI-based antiretroviral treatment. The main aim of this is to justify the inclusion of gag sequences in HIV-1 drug interpretation algorithms for managing patients on antiretroviral treatment. Although patients from all ages will be included, I do think that pediatric and adolescent and adult patients are unique sub-populations that need to be analyzed separately. That is also true for patients from low-to-middle income countries (vs. first-world countries). Although the authors will ultimately look at drug resistance mutations per se, which should not be impacted by age and country, there may be different adherence patterns (and consequently different levels of drug pressures) which may impact on the types of drug resistance mutations that are selected for (in PR and/or in gag). In addition, genotypic drug resistance data in adults may be scarcer than the data on paediatrics/adolescents, especially in low-to-middle income countries since PI-based regimens form the first-line regimen for pediatrics in these settings.

Some minor comments:

1. Please check typing as there are several instances of spaces missing between words.

2. In the Questions section under "Data Availability", please specify where the data will be made available.

3. In the Questions section under "Describe where the data may be found in full sentences: I would like to recommend that the website addresses of databases and search engines employed to obtain the data be added.

Reviewer #3: This systematic review protocol describes how the authors will set about collating information to identify HIV-1 Gag mutation associated with ritonavir-boosted protease inhibitors, according to viral subtypes. This is a very worthwhile study and the results should be very intriguing.

Some issues require further clarity:

1. Intervention – the first group will include patients receiving atazanavir, lopinavir and darunavir. Given the data search will extend to the year 2000, and that other PI have been used since that time, including nelfinavir, will patients receiving only the three PI’s mentioned, will other PI-based regimens be an exclusion criterion? Later in the protocol, indinavir is also mentioned.

2. Prevalence of gag mutations is defined as non-polymorphic mutations (<5%). However, as Gag mutations are not specifically defined, these mutations need to be relative to a reference sequence. Please clarify what will be used as the reference sequence.

3. As there are discrepancies between the Stanford mutation list and the IAS drug resistance list, please clarify which one will be used.

4. Treatment failure is defined as having an unsuppressed viral load (≥1,000 copies/ml). As treatment failure is inconsistently defined across different regions, and a first viraemic result sometimes considered as non-adherence, how will the analysis accommodate these differences. If any VL result ≥1000 copies/ml considered for inclusion, please clarify in the protocol.

5. Line 204 refers to duration of follow up. Is the absence of this data considered an exclusion criterion, as I predict this will be absent from a number of studies.

6. Line 91 suggest rephrasing this sentence to clarify that one gene is not “some”.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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HIV-1 Gag gene mutations, treatment response and drug resistance to Protease inhibitors: A systematic review and meta-analysis protocol

PONE-D-20-31760R1

Dear Dr. NKA,

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Kind regards,

Paul Spearman

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: