PONE-D-19-14981

A Prospective Randomized trial on Abacavir/lamivudine plus DArunavir/ritonavir or Raltegravir in HIV-positive drug-naïve patients with CD4<200 cells/uL (the PRADAR Study)

PLOS ONE

Dear Dr. Mussini,

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In addition to addressing the comments from the reviewers, please could you review the following:

1.  In the abstract it is stated 'the test and treat strategy is rarely applicable'; is this related to the study design and the use of ABC/3TC or RTG and do you think this strategy will become more applicable with modern ART and the strategy of the LAPTOP study? This should be revised.

2.  In the discussion section, please consider mentioning the LAPTOP study and how the approach differs from your study.

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Alan Winston

Academic Editor

PLOS ONE

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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: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

Reviewer #4: 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: There are only a few randomized clinical trials on antiretroviral head-to-head comparison between protease-inhibitor (PI) versus integrase-inhibitor (INSTI) based combination triple therapy. PRADAR was a multicentre, national (Italian), open label study and an attempt to fill this important data gap. The study design radically addressed the open question, whether standard combination ART should better contain an INSTI, or “best practice-PI”. Because the chosen study population was moreover the difficult-to-treat HIV-late presenters, with very low first measured CD4-cell counts (<200/µL), the study finally failed by trying to reach “a bridge too far”. Though the attempt was heroic, this report’s conclusions should not be in vain, as this may guide future RCTs to answer the yet open question.

The main problem of this study was the patient recruitment underperformance, reflected by the fact that only 46 individuals were randomized in three years – far from trial’s goal of 350. There are different reasons for this failure: apart from the challenging study population, that may often be deterred from a trial participation due to many reasons, there was another game changer occurring in the middle of the recruitment time – the publication of the START-study, as discussed. All antiretroviral therapy guidelines were subsequently changed to prompt treatment initiation; this diminished indirectly the potential study population.

The study addresses a major important study question - better INSTI or PI for late presenters? It anticipated the study question long before other major trials, i.e. currently under investigation (see NCT03696160). Though the report did not fully succeed, it should not hide its’ light under the bushel. Therefore, I consider the report on PRADAR as valuable and worth reading. Nevertheless, I recommend to consider the following minor issues:

1. Discussion, page 18/30, line 3, following, you wrote: “Indeed, due to the low number of subjects enrolled it was not possible to perform any comparative analysis between RAL and DRV/r.” – But you have performed comparisons! And you had interesting findings, e.g. on clinical adverse events and cholesterol differences between groups. – Please clarify.

2. Discussion, page 19/30, first lines/first para – please consider to discuss the following facts: in NEAT001-randomized clinical trial (NCT01066962), the raltegravir-containing arm did not perform as well as the standard-of-care arm containing darunavir/ritonavir plus two nucleosidal reverse transcriptase inhibitors, in the subgroup of patients with a CD4 cell count <200/µL. Similar findings were detected in patients with another actual dual regimen in naives: NCT02831764 & NCT02831673.

3. Discussion, page 19/30, lines 14 & following – see above remarks on START study findings release while PRADAR study recruitment.

4. Discussion, page 20/30, second para – you showed differences in week 48-outcomes of complete HIV-RNA suppression (<50 copies/mL) between arms, i.e. the primary end point (94.3 vs. 84.2%). Please consider to argue on the differences concerning the 50 copies/mL-threshold for PI vs. INSTI drug classes and to display as well the results for a 200 copies/mL-threshold, as the ACTG recommended this different limit of detection for studies on protease inhibitors.

5. Figure 1, page 27/30: please consider to include the reasons for 7 screening failures.

Reviewer #2: Good work by the authors. I agree it is difficult study to recruit to in the current environment. many other options are available and perceived as superior to the combinations you are trying to test.

in Your abstract ( in the last line) you stated: the rate of virologic success is similar to that described in the literature and very far from results of the recent trials in naïve patients.

this statement needs to be revisited in my view and quantified.

in the last line of your introduction: >500000 should be <500000.

Reviewer #3: • The paper by Mussini et al. reports on a randomized clinical tria which failed t recruit the goal of 350 patients with advanced HIV infection in order to compare an antiretroviral therapy consititing of either ABC/3TC+DRV/r or ABC/3TC+RAL. In total, onl 46 patients were included, n=22 in the RAL arm and n=24 in the DRV/r arm Thus, the study fails to provide sound and scientifically valid data to make any meaningful conclusions in terms of virological response or other endpoints. Little to nowthing can be said about these combinations for patients presenting late. Same The main conclussion of the authors is that late presenter are frequent but difficult to enroll in clincial trials.

• It is unfortunate that the study failed. At the same time, there is no report in the manuscript about how the study team at least tried to increase patient recruitment during study (proticol changes, increasing the number of study sites etc.)

• The time of recruitment is unclear. In the abstract, the authors state 3 years, in the discussion they state that they did nt expect to have such a low number of patients in 5 years.

Reviewer #4: A two arm non-inferiority randomized study was conducted to compare 48-week virological response of abacavir/lamivudine + darunavir/r vs abacavir/lamivudine + raltegravir in antiretroviral naive late presenter HIV patients. The target sample size was 350; although, due to slow accrual only 46 patients were enrolled. At 48 weeks a virologic success of 77.3% in raltegravir and 66.7% in darunavir/r was observed. Too few patients were enrolled to effectively constructed confidence bounds to test non-inferiority.

Minor revisions:

1- Specify the "parametric or non-parametric tests" that were used.

2- Cite the statistical software used for the analysis.

3- Table 1: In addition to frequencies, provide corresponding percentages for gender, risk factors and CDC stage. For age, HIV RNA, CD4 and CD8 provide the first and third quartiles.

4- Provide confidence intervals for the percentage estimates in the following sentence. “According to a snapshot algorithm, on the ITT population, after 48 weeks the proportion of treatment success was 77.3% in the RAL group and 66.7% in the DRV/r group.”

5- Instead of calculating the IQR, provide the first and third quartiles since they are more informative.

6- Provide numerical p-values rather than “NS.”

7- Include a table summarizing the adverse events by treatment arm. Include percentages corresponding to the frequencies.

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Reviewer #1: No

Reviewer #2: Yes: Elbushra Herieka

Reviewer #3: No

Reviewer #4: No

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A Prospective Randomized trial on Abacavir/lamivudine plus DArunavir/ritonavir or Raltegravir in HIV-positive drug-naïve patients with CD4<200 cells/uL (the PRADAR Study)

PONE-D-19-14981R1

Dear Dr. Mussini,

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With kind regards,

Alan Winston

Academic Editor

PLOS ONE

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