PONE-D-24-10391First-line antiretroviral therapy initiation for newly diagnosed people with HIV in the Netherlands: a retrospective analysis from 2016 to 2020.PLOS ONE

Dear Dr. Oosterhof,

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.

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ACADEMIC EDITOR:

MAJOR COMMENTS

Table 4. Adherence rate Here and so on in many other cases, the term adherence might be misunderstood in the manuscript. According to WHO, adherence “is the extent to which a person's behavior – taking medication, attending scheduled clinic appointments, following a diet and/or changing lifestyle – corresponds with care and treatment plans”. Compliance rate or compliance with Dutch guidelines could be more suitable. On the other hand, adherence is most appropriately used in Discussion (lines 258, 262, 263).

In line with the third observation done by authors in Discussion (lines 282-287), I missed a detailed economic impact of the generic drugs. This calculation could be done from percentages known (and depicted in Table 3). How much decline can be attributed to the availability of generics? How much can be attributed to other factors in addition to the indicated small reduction in the price of STRs? For instance, some regimens (BIC/TAF/FTC, EVG/c/TAF/FTC, DRV/c+TAF/FTC,…) contribute unequally throughout the period. I recommend perform this calculation, which would improve the conclusions obtained.

Figure 3 (cited in line 205) is missing.

MINOR COMMENTS

1. Line 165. Three of the 27 treatment centers  Better: Three out of the 27…
2. Centers firstly listed in Table 4 must fully be depicted as supplementary material. 
3. The results section includes some statements discussing the findings (from line 129 to 133; from line 151 to 154). They should be allocated in Discussion section.
4. Table 3. Percentage of patients on DHHS-recommended initial regimens from 2016 – 2020 Percentages are shown only for each regimen but they must be given for all the options within them. In addition, the heading of this table may simply be “Patients on DHHS-recommended…”.

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Academic Editor

PLOS ONE

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Additional Editor Comments:

This manuscript retrospectively analyzed the antiretroviral therapy of initiation for naïve HIV patients diagnosed between January 2016 and December 2020. Type and agreement with guidelines by Dutch Department of Health and Human Services were assessed as well as monthly cost.

It is a very interesting overview of that topic in the Netherlands. The manuscript is well-written but I have some major and other minor comments from myself and the reviewers, which should be addressed as much as possible before publication.

MAJOR COMMENTS

Table 4. Adherence rate Here and so on in many other cases, the term adherence might be misunderstood in the manuscript. According to WHO, adherence “is the extent to which a person's behavior – taking medication, attending scheduled clinic appointments, following a diet and/or changing lifestyle – corresponds with care and treatment plans”. Compliance rate or compliance with Dutch guidelines could be more suitable. On the other hand, adherence is most appropriately used in Discussion (lines 258, 262, 263).

In line with the third observation done by authors in Discussion (lines 282-287), I missed a detailed economic impact of the generic drugs. This calculation could be done from percentages known (and depicted in Table 3). How much decline can be attributed to the availability of generics? How much can be attributed to other factors in addition to the indicated small reduction in the price of STRs? For instance, some regimens (BIC/TAF/FTC, EVG/c/TAF/FTC, DRV/c+TAF/FTC,…) contribute unequally throughout the period.

Figure 3 (cited in line 205) is missing.

MINOR COMMENTS

165 period. Three of the 27 treatment centers Three out of the 27…

Centers firstly listed in Table 4 must fully be depicted as supplementary material.

The results section includes some statements discussing the findings (from line 129 to 133; from line 151 to 154). They should be allocated in Discussion section.

Table 3. Percentage of patients on DHHS-recommended initial regimens from 2016 – 2020 Percentages are shown only for each regimen but they must be given for all the options within them. In addition, the heading of this table may simply be “Patients on DHHS-recommended…”.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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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: 1. 114-123: Overuse of passive voice in this paragraph, should be changed to active voice to be better understood.

2. Discussion: I miss the explanation of why there is a greater use of TDF vs TAF in this population in spite of having, the second one, a better clinical profile of adverse events. This could affect the prize of HIV burden in long term. Try to explain this in few words.

3. Bibliography mistakes:

- 417: avoid (London, England).

- 422: avoid (London, England).

- 435: avoid dots.

- 437: 2021. 2021.

- 438: c2023.

- 440: c2023.

- 442: Netherlands2022

- 452: avoid (London, England).

- 480: BMJ Open.

Reviewer #2: Oosterhof et al analyze the initial ART regimens in the Netherlands in a large cohort of 3,445 HIV naïve patients starting ART between January 2016 and December 2020.They observed an increasing tendence to prescribe integrase inhibitor containing regimens from 77.3% in 2016 to 87.8% in 2020. Most patients received STR regimens although with a decreasing rate from 81.3% in 2016 to 60.3% in 2020. The gMTRs showed a steady increase from 17.8% in 2018 to 37.8% in 2020. This fact implied a cost reduction of the first-line ART regimen per patient from 17.8% in 2018 to 37.8% in 2020. The adherence rate to DHHS-recommended initial regimens increased from 82.8% in 2016 to 90.0% in 2020, not influenced by the gMTRs prescription increase.

Major points

1.This work reinforces previous studies showing that ART adherence rate is not always linked to STR and this is a key point of the manuscript. However all the enrolled patients received their ART once-daily (QD regimens) and this is important to emphasize in the discussion. The number of intake moments is important with perfect adherence linked to once-daily ART.

2.The fact that the STR and gMTR prescription data provided here represents the situation at the start of HIV therapy and not on the persistence of STR and gMTR is the main pitfall of the study. Could you provide some data on the number of ART switch per patient or study center and analyzed year ?

Minor points

1. I do not see why 100% adherence to DHHS recommended regimens is not desirable. (pages 17, line 241,and 18, line 244.250). Perhaps this sentence could be changed to “ difficult to obtain” due to pregnancy-due specific ART regimens and some study protocols that pushed the ART from the DHHS recommendations.

2. “Finally , another limitation was that we analyzed the prescription of ART regimens rather than specific formulation” (Page 21, lines 326-327).Do you mean single antiretrovirals and not combined SRTs and gMTRs regimens when to mention specific formulations ?

Reviewer #3: The authors present a retrospective study on first-line antiretroviral therapy for people newly diagnosed with HIV in the Netherlands. The article is well written and provides data of interest.

Two minor consdierations

- Please consider improving Figure 2. It is complex to interpret

- Page 16, line 205: costs per person per month for initiating ART (Figure 3). I cannot find this figure

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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First-line antiretroviral therapy initiation for newly diagnosed people with HIV in the Netherlands: a retrospective analysis from 2016 to 2020.

PONE-D-24-10391R1

Dear Dr. Piter Oosterhof, PharmD,

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Kind regards,

Carmen María González-Domenech, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for properly addressing all the issues pointed by the reviewers and the academic editor. In addition, the minor mistakes noticed have also been amended. Thus, your manuscript is ready to be publised by PLoS One journal in the current version. Thank you for submitting your valuable work to our journal.