PONE-D-23-09503A Phase I Study of Intra-anal Artesunate (suppositories) to Treat Anal High-grade Squamous Intraepithelial LesionsPLOS ONE

Dear Dr. Fang,

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Reviewers' comments:

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Comments to the Author

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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: 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: The authors conducted a 3+3 dose escalation Phase I clinical trial to evaluate the safety and tolerability of artesunate suppositories in the treatment of patients with biopsy-proven HSIL. Nineteen patients were enrolled for evaluation, and the maximal tolerated dose was determined at 400 mg, administered in 3 cycles. Overall, the manuscript was well written. I have a few comments on the statistical analysis and evaluation.

1. After determine the maximal tolerated dose at 400mg, there is no extension cohort at this dose level to evaluate the key secondary outcomes such as complete histologic regression, clearance of dateable HPV genotypes. Need to put into the discussion for the limitation.

2. For the participants enrolled in the 600 mg arm, only one experienced grade 2 nausea, then the authors decided that Nausea was considered dose-limiting at the 600 mg dose, why not enroll 3 more participants into the 600 mg arm following the standard 3+3 scheme?

Reviewer #2: The study is an early phase trial on the efficacy of artesunate suppository for anal HSIL.El estudio se trata de un ensayo en fase precoz sobre la eficacia del artesunato en supositorio para HSIL anal. es interesante y novedoso, y presenta otra opción en el tratamiento de la displasia anal de alto grado. One of the points that concerns me in this study is that more than 50% of the bibliographic references, to be exact 56.25% are more than 10 years old, some of them close to 20 years old. I recomend to read and includ this reseacrh for example: Hidalgo-Tenorio C,et al. Risk factors for ≥high-grade anal intraepithelial lesions in MSM living with HIV and the response to topical and surgical treatments One. 2021 Feb 3;16(2):e0245870; or this one: Fuertes I, et al The effectiveness and tolerability of imiquimod suppositories to treat extensive intra-anal high-grade squamous intraepithelial lesions/warts in HIV-infected individuals. Int J STD AIDS. 2019 Oct;30(12):1194-1200. The discussion is very poorly elaborated, it should be ostensibly improved if it is finally published.

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Reviewer #1: No

Reviewer #2: No

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A Phase I Study of Intra-anal Artesunate (suppositories) to Treat Anal High-grade Squamous Intraepithelial Lesions

PONE-D-23-09503R1

Dear Dr. Fang,

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,

Diane M Harper, MD, MPH, MS

Academic Editor

PLOS ONE

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