PONE-D-20-22518

Antiviral Kinetics of Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate over 24 Weeks in Women of Childbearing Potential with Chronic HBV

PLOS ONE

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'Calvin Pan has received research grants from Gilead and Merck. He also serves as a consultant or advisor for Gilead, and speakers’ bureau for Gilead, Abbvie, and Intercept. Ting-Tsung Chang and Si Hyun Bae declare no conflicts of interest. Wai Kay Seto serves on the advisory boards of Gilead, Abbvie and CSL Behring, and is a speaker for Gilead, AbbVie and Mylan. Maurizia Brunetto has received research grants from AbbVie, BMS, MSD, has served on advisory Boards for AbbVie, Gilead, Janssen; Roche, and has served as a speaker for AbbVie, Gilead, MSD. Carla S. Coffin has served as an investigator or received research grants from GlaxoSmithKline, Gilead, Arbutus Biopharma, Bristol-Myers Squibb, has received educational grants from Merck, Gilead, Janssen, has served on advisory boards for Merck, Gilead, GlaxoSmithKline, has served on CTPC committees for Springbank, and has participated as a primary investigator in clinical trials for Gilead, Springbank, Transgene, and Janssen. The following authors are employees of Gilead Sciences and hold stock interest in the company: Susanna Tan, Shuyuan Mo, John Flaherty, and Anuj Gaggar. Mindie H. Nguyen has received research support from Gilead and Pfizer, has served on advisory boards and/or as a consultant for Novartis, Springbank, Janssen, Gilead, Eisai, Bayer. Exact Science, and LAM. Mustafa Kemal Çelen has no conflicts of interest to disclose. Alexander Thompson has received research support from Gilead, AbbVie, and Merck, and has served on advisory boards and/or as a consultant for Gilead, AbbVie, Merck, BMS, Eisai. Edward J. Gane has served as a consultant or advisor for Gilead, AbbVie, Roche, Janssen and at speakers’ bureaus for Gilead and AbbVie.'

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Reviewer #1: Partly

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: PONE-D-20-22518: statistical review

SUMMARY. This is a secondary analysis of subjects with chronic hepatitis B, enrolled in two previous studies and respectively treated with tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF). It compares the proportion of subjects who reach the viral supression target (HBV DNA <200,000 IU/mL) at weeks 12 and 24 of the follow-up period. Supplementary analyses are made by considering alternative viral supression targets in subgroups. In a second part of the study, logistic regression analysis is performed to detect significant risk factors for failure to achieve the viral suppression target. While I have nothing to say about the second part of the study (methods are correct and results are clearly described and appropriately interpreted), I have a couple of concerns about the first part of the analysis: see major issues 1 and 2 below.

MAJOR ISSUES

1) One main finding of the study is that TAF and TDF have a similar effect on viral suppression at weeks 12 and 24, as described at the beginning of page 11. However, it looks like the difference between proportions has not been tested (ot it has, but results have not been reported ...). A two-sample test for proportions can be performed to show that, separately at weeks 12 and 24, proportions are not significately different. Or, perhaps more elegantly, an ANOVA logistic model can be estimated to perform a simultaneous test on both the 12th and the 24th week.

2) Figures 1 and 2 display the cumulative proportion of subjects who reach the suppression target at several weeks. I wonder why we shoud limit our attention to these two weeks when we could compare the two curves as a whole. For example, taking the complementary cumulative proportions (e.g. 1-p_w, where p_w is the cumulative proportion at week w), we obtain two survival curves that can be compared by a nonparametric logrank test, without the need of specific parametric assumptions. The authors should either perform this analysis or, alternatively, explain why weeks 12 and 24 are the only relevant weeks in this study.

Reviewer #2: The manuscript entitled “Antiviral kinetics of TAF and TDF over 24 weeks in women of childbearing potential with chronic HBV” addresses an important topic in optimizing chronic HBV treatment among women of childbearing potential, as pregnant women were previously excluded from participation in clinical trials. The Introduction states that ‘several investigator-sponsored trials evaluating TAF for PMTCT of HBV are underway with results expected within a few years.” It is unclear to this reviewer why it takes several more years for these important trials to complete (given that the follow-up period for HBV is relatively short).

The present study provides reassuring data on early viral suppression in women of childbearing age and, as expected, TAF was well tolerated and showed less impact on renal and bone parameters than TDF. These findings are important and do support the ongoing clinical trials of TAF in pregnant women for HBV PMTCT. The reviewer notes that 4 coauthors are employed by the company (Gilead Sciences) and many coauthors have potential conflicts of interest; however, these potential conflicts have been transparently reported.

Following are several comments and suggestions for the authors:

(1) The authors mention current HBV care and treatment guidelines from the various professional liver societies around the world (with substantial variations noted in these regional guidelines). However, the authors fail to include the WHO HBV guidelines. On World Hepatitis Day (July 2020), WHO published updated guidelines for the PMTCT of HBV – which are highly relevant to the present article.

(2) Two systematic reviews prepared for the latest 2020 WHO HBV guidelines have appeared in Lancet Infectious Diseases (published online August 2020; in hard copy, current issue): Boucheron et al; and Funk et al. These 2 systematic reviews provide relevant summary data for the Introduction and Discussion sections of your paper.

(3) First sentence “Worldwide, over 2 billion are infected with HBV …” (note this doesn’t seem accurately worded; over 2 billion people have become infected at some time during their lifetime). Chronic HBV infections worldwide are estimated by WHO at 257 million persons (see World Hepatitis Report, WHO, Geneva, 2017). The cited paper by Polaris – your reference 2 - is a relative outlier (‘up to 292 million’) among several published HBV modeling papers from 4-5 different groups. Your reference 1 (Schweitzer et al) estimated the number of people living with HBV infection at 240 million. The WHO estimate was a consensus estimate (involving many of the same investigator groups) – this reviewer recommends using the WHO (consensus) estimate.

(4) Intro, page 6, last para: Could you mention anything on the price differential between TAF and TDF? In practice, this will be an important determinant of use.

(5) “Currently approved in over 70 countries worldwide, including China, Japan, S Korea, Taiwan, and Hong Kong.” This seems overly focused on one area of the world. How about Europe, Africa, S America? (or simply delete individual countries).

(6) Page 7, line 3: ‘…same active moiety”. It seems accurately worded in this context. Just keep in mind, many people - like this reviewer - may not be familiar with ‘moiety’.

(7) Page 7, line 5: “Investigator-sponsored trials …” - not sure I understand this. Do you mean “investigator-initiated”? Usually each trial has a financial sponsor (e.g., NIH, a company or a foundation).

(8) Page 8, line: “2 identically designed, prospective, randomized trials…” However, we learn that one trial focused on HBeAg-positive patients and the other on HBeAg-negative patients. Therefore, I think ‘identically designed’ is incorrect.

(9) The study design included women of childbearing potential as ‘females 18-49 years of age’ – with a median age of 35 years. Thus, the average age in your study is higher than the average age of pregnant women in most countries (around 25-26 years of age) though this is changing. Not sure if this 10-year age difference might change any of the findings – I suggest including it among the study limitations.

(10) Discussion: page 13, line 12-13: Does your study provide any data on HBV viral load suppression ‘less than 12 weeks’ after initiation of HBV treatment (either TAF or TDF)? Such data would be very helpful.

(11) Discussion, end of para 1: Again, it would be helpful to include the updated 2020 WHO HBV guidelines in your Discussion. In many countries (e.g., in Africa, Latin America, many countries in Asia outside China), these would be the ones used.

Overall, this is an important paper and the findings among women of childbearing potential appear quite unique in the HBV literature.

Here are a few minor issues:

1) Reference 3 lacks information on year and pages.

2) Table headings need more information: for example, they should include information about the study population/year of the study cohorts included. Currently, the table headings cannot be interpreted or ‘stand on their own’.

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Reviewer #1: No

Reviewer #2: No

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Antiviral kinetics of tenofovir alafenamide and tenofovir disoproxil fumarate over 24 weeks in women of childbearing potential with chronic HBV

PONE-D-20-22518R1

Dear Dr. Pan,

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