PONE-D-24-08936Assessment of risk factors for virological nonsuppression following switch to dolutegravir and lamivudine, or bictegravir, emtricitabine, and tenofovir alafenamide fumarate in a real-world cohort of treatment-experienced adults living with HIVPLOS ONE

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Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: The study assessed the real-world effectiveness and safety of switching to either BIC/FTC/TAF or DTG/3TC in a real-world setting, examining both PWH with virological suppression and those without it at the time of switch. The results filled in the gaps left by clinical trials, which typically only included PWH who already had virological suppression. I have some comments as follows.

Major comments:

1. Introduction:

The authors stated that the study aimed to explore the risk factors associated with virological non-suppression following a 48-week period of secondary INSTI-based ART. However, it's important to note that secondary INSTI-based ART includes more than just BIC/FTC/TAF and DTG/3TC.

2. Methods:

The study included PWH who were switched to either BIC/FTC/TAF or DTG/3TC but excluded those who discontinued ART, were lost to follow-up, or passed away from the final analyses. These exclusion criteria should be explicitly stated in the study's methodology. Moreover, PWH who discontinued ART, were lost to follow-up, or passed away could potentially have experience virological non-suppression. Excluding these individuals may introduce bias into the analysis.

3. Results:

(1) In the methodology, the authors indicated that the study was conducted from March 2019 to January 2022, with individuals followed up until January 2023. However, in the results, individuals were screened for inclusion between October 2019 and January 2023.

(2) A logistic regression model was used to clarify the risk factors associated with virological non-suppression. However, the authors included certain variables in the model that might have collinearity, such as a PVL >100,000 cp/mL, a history of virological failure ≥2 times, and PVL <50 cp/mL within the past 3 months before switch. It's crucial to inquire whether the authors assessed collinearity beforehand.

(3) The authors concluded that the effectiveness of DTG/3TC and BIC/FTC/TAF was comparable based on the findings from the multivariable analysis. However, it's still essential to compare effectiveness outcomes, which included virological suppression, low-level viremia, viral blip, and virological failure, between DTG/3TC and BIC/FTC/TAF.

(4) The authors mentioned that no individual was detected to have acquired drug RAMs during follow-up. How many individuals had viremia levels sufficient for detecting RAMs?

(5) Since the tables are not included in the manuscript, I'm having difficulty reviewing the accuracy of the results.

4. Discussion:

The findings that positive HBsAg was related to virological non-suppression should be discussed.

Minor comments:

1. Abstract:

(1) Line 8: A total of 1086 patients were included, 44 patients (4%) with VS at week 48.

-> Please check the number of patients with virological suppression (VS).

(2) In line with the study title, the conclusion should emphasize the impact of various ART regimens rather than focusing on subsequent RAMs.

2. Please standardize the terminology for HIV-1 RNA levels throughout the manuscript. Currently, different terms are used interchangeably, including HIV-1 RNA levels, HIV-VL, plasma viral load, etc.

3. Please ensure that the full names of abbreviations are written out only once, when they first appear in the text.

4. Introduction:

Paragraph 3: Most studies predominantly included treatment-naïve or virologically suppressed patients,

-> Please specify the types of ART studied in the mentioned studies.

5. Methods:

Considering the correlation between positive HBsAg and virological non-suppression, and the decision not to switch PWH coinfected with HBV to DTG/3TC regimen, do you think positive HBsAg should be listed as an exclusion criterion?

6. Results:

(1) Did those 44 patients with detectable viral loads at week 48 continue to use DTG/3TC and BIC/FTC/TAF?

(2) Fig 2. Changes in body weight and blood lipid from baseline to week 48 in the PP-E analysis.

-> What does PP-E analysis stand for?

7. Discussion:

(1) Paragraph 3: "TANGO" should be capitalized.

(2) Paragraph 3: Our real-world study included those with detectable viral loads at the switch (13.2%).

-> However, the results showed that 19 (2%) had PVL ≥100,000 cp/mL and 26 (2%) had LLV at the switch.

(3) Paragraph 4: which demonstrated that the incidence rate of developing LLV was 4.2 per 100 person-years of follow-up in the BIC/FTC/TAF group and 2.3 per 100 PYFU in the DTG/3TC group [incidence rate ratio = 1.83; p = 0.09].

-> The data are not presented in the results part. Additionally, to compare incidences between studies, the authors should briefly list some data from previous studies.

Reviewer #2: PLOS ONE

Assessment of risk factors for virological nonsuppression following switch to dolutegravir and lamivudine, or bictegravir, emtricitabine, and tenofovir alafenamide fumarate in a real-world cohort of treatment-experienced adults living with HIV

Manuscript Number: PONE-D-24-08936

The work presents relevant results from a clinical point of view and adds more information about the change to BIC/FTC/TAF or DTG/3TC from other antiretroviral treatment regimens.

The methodology is correct as well as the statistical analysis. The conclusions are appropriate according to the results presented.

The article is presented in an intelligible fashion and is written in standard English although I am not native and cannot be conclusive in this regard

I believe that the article can be accepted with minimal changes that are suggested below:

Abstract:

VS: Acronyms must be defined. I understand that 44 patients (4%) were virological non suppressors. (VNS)

A switch should be distinguished from undetectability vs. virological failure or treatment suspension and restart with a new regimen.

No significant difference was found between the DTG/3TC and BIC/FTC/TAF regimens (AOR: 1.32, 95% CI 0.59–2.94) (it is not known in the abstract which the OR is favorable towards). That is, using BIC/FTC/TAF multiplies the risk of failure compared to DTG/3TC by 1.32 (with DTG/3TC being the reference) or using DTG/3TC multiplies the risk of failure compared to BIC/FTC/TAF by 1.32

Introduction

The primary objective of this study is to investigate the risk factors associated with virological nonsuppression outcome with secondary INSTI-based ART after a 48-week period. The objective must be defined the population in which the risk factors for virological non-suppression will be analyzed (Patients in Switch). Do it in PICO format. Population (Switch), intervention will change to DTG/3TC (intervention) or BIC/FTC/TAF (comparison) and result (Virological non suppression)

Material and methods.

In exclusion criteria..., were pregnant women excluded? Were patients with HBSag+ not excluded? If not, Were any of them assigned to DTG/3TC?

…with “virological non-suppression” (This terminology should be consistent throughout the manuscript)

In the analysis it must be clear if the end point is through a “snapshot” at week 48 (regardless of what happens up to week 48 or if a confirmed virological failure is performed in a second sample if there is one).

The authors comment: “Virological non-suppression included: LLV, viral blip, and VF”.

In the case of a patient with a VL of 75 copies/ml at w 48 and having previously VL < 50 copies at all times, would it be defined as VF without having analyzed a second VL to know if it is a blip?

Statistic analysis.

Why were parametric tests not carried out instead of non-parametric ones? You had samples of more than 30 subjects in each group. Was a paired data study ever carried out? (McNemar and Wilcoxon? Were they necessary?

In logistic regression models, it would be advisable to add model calibration using the Hosmer-Lemeshow test and Nagelkerke's R2 to assess the proportion of VNS that is explained by the independent variables.

…”Furthermore, 62 (6%) had the record of virological failure more than 2 times before switching”. (There are few patients which can hinder the probability of having a model with sufficient power to achieve accurate predictions (with narrow 95% CI)

Failure was seen in 46 patients, which limits models preferably with no more than 5 adjustment variables...

Just comment in limitations

Results:

Do we know the percentage with RNA+ in those with HCV+ serology?

…Their mean age (SD) was 39.8 (± 9.9)… perhaps better median (p25-p75) years, and 173 (16%) were > 50 years old.

…The mean follow-up time since initiating ART was 6.0 (± 3.7) years… (best median p25-p75).

…The mean CD4 counts was 633 cells/µL (± 307); would be better median and p25-p75,

…19 (2%) had HIV-1 RNA levels ≥100,000 copies/mL, and 26 (2%) had LLV. Did the rest of the patients start with a VL < 50 copies/mL?

Loss of follow up, deaths and discontinuations must be made according to the change to DTG/3TC or BIC/FTC/TAF. A figure would be recommended

Figure 1: the patients who were switched to DTG/3TC or BIC/FTC/TAF should be divided and in the figure express the number who died, discontinued or were lost to follow-up in each group, as well as the number of DTG VNS /3TC or BIC/FTC/TAF

Table 1. Table 1, 2 and 4 are correct.

In Table 3, the reference population is unknown. Especially between DTG/3TC and BIC/FTC/TAF.

Adverse events and causes leading to discontinuation

It would be advisable to create a Kaplan-Meier curve analyzing the discontinuation rate in each arm (DTG/3TC vs TAF/FTC/BIC).

Discussion

Regarding adverse effects, I would comment that surely many of the patients with ABC/3TC/DTG switched to DTG/3TC, which makes it unlikely that clinicians will attribute side effects to the new regimen.

On the contrary, surely most patients from TAF/FTC/EVG/c were transferred to BIC/TAF/FTC, which makes it more likely to attribute toxicity if it exists. Despite this, no greater toxicity was observed in one arm than the other.

Insist again on the way in which the analysis is performed at week 48 (Is it a confirmed virological failure, is it a blip or is it a low level replication...?)

Comment on: HBsAg positive patients should not switch to DTG+3TC due to insufficient HBV control?

Comment in the discussion about this…:

…Furthermore, overall adverse effects were generally similar between groups, but increased weight or obesity was the leading cause of discontinuation in patients switching to a regimen of BIC/FTC/TAF than those switching to DTG/3TC… (Comment: some clinicians attribute increased weights to TAF which may justify more adverse effects or discontinuations of BIC/FTC/TAF without solid data based on clinical trials yet.).

Conclusions

In the conclusions I would say something like:

“In conclusion, our study suggests that the effectiveness and safety profiles of switching to DTG/3TC and BIC/FTC/TAF were comparable in treatment-experienced adults with HIV. The presence of high viral loads, frequent virological failure before the switch and positive HBsAg status might impact the benefits of these regimens in the short term of follow-up”

Bibliografía,

I would include a similar study already evaluated in this journal such as:

Mendoza I, Lázaro A, Espinosa A, Sánchez L, Horta AM, Torralba M. Effectiveness, durability and safety of dolutegravir and lamivudine versus bictegravir, emtricitabine and tenofovir alafenamide in a real-world cohort of HIV-infected adults. PLoS One. 2023 Sep 29;18(9):e0291480. doi: 10.1371/journal.pone.0291480. PMID: 37773939; PMCID: PMC10540944.

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Reviewer #1: No

Reviewer #2: Yes: Miguel Torralba MD PhD.

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PONE-D-24-08936R1Assessment of risk factors for virological nonsuppression following switch to dolutegravir and lamivudine, or bictegravir, emtricitabine, and tenofovir alafenamide fumarate in a real-world cohort of treatment-experienced adults living with HIVPLOS ONE

Dear Dr. cheng,

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.  We kindly ask you to address the minor comments raised before the manuscript can be accepted. 

Please submit your revised manuscript by Nov 22 2024 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Benjamin Chimukangara

Academic Editor

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.

Additional Editor Comments:

Thank you for the revised manuscript which provides relevant data for virologic outcomes among treatment experienced individuals switching to DTG and BIC regimens. After additional reviews, some minor comments were raised that require your attention. May I kindly ask you to revise the manuscript in line with comments from the reviewers. To help rapidly assess your revised version, please highlight any changes made in the revised manuscript and include specific page numbers in your responses to the reviewer comments. Thank you.

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: (No Response)

Reviewer #2: 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 #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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 #1: Yes

Reviewer #2: Yes

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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

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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 #1: Some issues I previously commented on have been improved in this revised manuscript. However, there are still some aspects that require revision.

1.Abstract: The identified factors associated with VNS should include both "record of virological failure ≥2 times" and "baseline HIV RNA >50 cp/ml". Please correct the inconsistencies between the AOR and 95% CI in the text and Table 3.

2.Introduction:

Paragraph 3: The authors stated "Most studies predominantly included treatment-naïve or virologically suppressed patients..."

-> Please specify the types of ART regimens used in the studies involving treatment-naïve or virologically suppressed patients and cite the relevant references. This would help improve the manuscript by highlighting the research gap.

3. Results:

(1) "Between October 2019 and January 2023, a total of 988 PWH were screened. We included 1,086 eligible individuals who switched their ART regimen to BIC/FTC/TAF or DTG/3TC. (Fig 1)"

-> This could be improved by stating that you first screened 1,086 individuals and then included 988 after excluding those who did not meet the inclusion criteria.

(2) Please unify the decimal places for data in the Results and Tables.

(3) For the 35 individuals not achieving VS, please describe how many had VF and how many had LLV. In the response letter, the authors mentioned that 7 individuals had HIV RNA >1,000 copies/mL, which was sufficient for detecting RAM, while the remaining 28 had HIV RNA levels between 50 and 1,000 copies/mL. This description should be added to the manuscript.

(4) Table 1: Please check if the following values are correct:

Heterosexual contact 80(7%)

Others 0 (2%)

CD4 counts <200 cells/uL 5 (9%)

(5) "Among PWH switching to DTG/3TC or BIC/FTC/TAF who had pre-existing K65R with or without M184V/I before the switch, all 3 out of 3 (100%) and 4 out of 4 (100%)"

-> In Table 2, a total of 6 PWH had pre-existing K65R, not 7.

(6) "However, 1 out of 158 (65.76%) patients with undetectable viral loadsVS at switch failed to maintain an HIV RNA of <50 copies/mL at week 48. For patients with M184V/I, the median duration of previous undetectable viral loadsVS before switch was 3.6 years (IQR: 2.5-5.5)."

-> These sentences would be clearer if included within the same paragraph related to PWH with pre-existing M184V/I.

(7) Please revise the inconsistency between the AOR and 95% CI in the text and Table 3.

(8) "The most common adverse events (AEs) in the DTG/3TC group were..." "The most common AEs leading to discontinuation in the BIC/FTC/TAF group were..."

-> It seems that the authors collected "AEs and causes leading to discontinuation" rather than just "AEs." Please clarify what was collected in the Methods section.

(9) The most common AEs "and causes" leading to discontinuation in the BIC/FTC/TAF group should also include nausea/diarrhea (0.8%).

(10) Table 4:

- Please check if the following value is correct: drug drug interaction 1 (0.)

- Could the authors provide an explanation for "completed LTBI treatment, then shifted back to previous ART" ?

4. Others:

Throughout the manuscript, "HIV RNA" should be revised to "HIV RNA level."

Reviewer #2: Minor Comments

In the abstract and results, the authors state:

"Furthermore, DTG/3TC was noninferior to BIC/FTC/TAF in achieving HIV RNA < 50 copies/mL (-10% noninferiority margin) in the per-protocol analysis (proportion of responders, 98.2% vs 95.0%, respectively; adjusted treatment difference [95% CI], 3.2% [0.7% to 5.3%])."

However,

In switch studies (such as the one conducted by the authors), it is customary to analyze the primary objective of demonstrating noninferiority by detecting virologic failure. In general, the usual delta used by regulatory agencies is 4%. Given that the majority of subjects in the study start with VL < 50 copies/mL, the delta that should not be exceeded is the 4% virologic failure, not the 10% therapeutic success proposed by the authors. This 10% is typical when attempting to demonstrate noninferiority in studies with naïve patients. In this case (naïve patients), the objective is not failure but therapeutic success.

My recommendation is that if the goal is to demonstrate the noninferiority of DTG/3TC vs BIC/FTC/TAF using BIC/FTC/TAF as the reference regimen, the upper limit of the 95% confidence interval should not exceed the 4% virologic failure against TAF.

As I understand it, 11 out of 508 patients fail with DTG/3TC, and 24 out of 480 patients fail with BIC/FTC/TAF.

According to these results (provided by the authors in Table 1), the risk difference for virologic failure is -2.8% in favor of DTG/3TC (95% CI: -5.159, -0.5103; p= 0.008)). Therefore, not only is the noninferiority of DTG/3TC versus BIC/FTC/TAF demonstrated (since the upper limit of the 95% CI does not reach +4%), but the superiority of DTG/3TC is also demonstrated, as the 95% CI does not cross 0% in the difference in virologic failure rates between the two regimens.

In the statistics section, I would note that the Hosmer-Lemeshow test is used to analyze the calibration of the model, and the Nagelkerke R2 is used to assess the percentage of VNS explained by the independent variables. These results are not shown in the article.

The introduction and materials and methods sections are correct.

In the results section, it states:

"14 (1%) had HIV RNA levels ≥100,000 copies/mL, 22 (2%) had LLV, and 875(89%) had VS at switch." This totals 1+2+89%, which sums to 92%. What about the missing 8%?

Before comparing the patients who failed with those who did not fail in Table 1, I would include a table comparing the DTG/3TC and BIC/FTC/TAF groups.

In the paragraph: "Moreover, the incidence rate of developing LLV was 3.5 per 100 person-years of follow-up (PYFU) in the BIC/FTC/TAF group and 2.2 per 100 PYFU in the DTG/3TC group [incidence rate ratio (IRR) = 1.64, 95% CI, 0.77-3.49].", I would add the "p-value."

In the discussion, I would mention as a limitation that the study was conducted through a per-protocol analysis and not by intention-to-treat.

The conclusion is correct.

The bibliography seems appropriate.

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Reviewer #1: No

Reviewer #2: Yes: Miguel Torralba

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PONE-D-24-08936R2Assessment of risk factors for virological nonsuppression following switch to dolutegravir and lamivudine, or bictegravir, emtricitabine, and tenofovir alafenamide fumarate in a real-world cohort of treatment-experienced adults living with HIVPLOS ONE

Dear Dr. cheng,

Thank you for addressing all the comments raised by the reviewers. Please make these minor revisions before we reach a final decision on the manuscript.

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Benjamin Chimukangara

Academic Editor

PLOS ONE

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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.

Additional Editor Comments:

General comments

Please be consistent with the way the < and > signs are used. For example, in introduction, "HIV RNA levels > 50 copies/mL at 6 months after starting therapy and confirmed HIV RNA levels > 50 copies/mL with previously undetectable HIV RNA levels are defined virological failure [2]." Then in another sentence, "This includes both low-level viremia (LLV, HIV RNA levels <50–1000 copies/mL) and virological failure (VF, HIV RNA levels >1000 copies/mL)." I would suggest deleting the space after the sign as done in the second example, and being consistent throughout the manuscript.

Results

I would suggest rephrasing to say, "Between October 2019 and January 2023, we first screened 1,086 individuals and then included 988 individuals who switched their ART regimen to BIC/FTC/TAF or DTG/3TC, after excluding those who did not meet the inclusion criteria.

Please consider revising the sentence, "It's worth noting that these 7 patients already achieved VS at baseline." It is still unclear how the patients were 7 if there were 3 in each group with K65R. Also please use the words "It is.." rather than "It's ..."

For clarity, please include a footnote under table 4 for "completed LTBI treatment, then shift back to previous ART, n (%)", to note that "After completing LTBI treatment, some patients preferred to switch back to their previous ART regimen.

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Reviewers' comments:

N/A

[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.]

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Assessment of risk factors for virological nonsuppression following switch to dolutegravir and lamivudine, or bictegravir, emtricitabine, and tenofovir alafenamide fumarate in a real-world cohort of treatment-experienced adults living with HIV

PONE-D-24-08936R3

Dear Dr. Chien-Yu Cheng,

We’re pleased to inform you that your manuscript has been considered scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Congratulations.

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Kind regards,

Benjamin Chimukangara

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

None

Reviewers' comments:

None