Short-Term Peg-IFN α-2b Re-Treatment Induced a High Functional Cure Rate in Patients with HBsAg Recurrence after Stopping Peg-IFN α-Based Regimens
, Yikai Wang 1, Dandan Cui 1, Yan Tian 1, Rui Lu 1, Chenrui Liu 1, Mei Li 1, Yaping Li 1, Ning Gao 1, Zicheng Jiang 2, Xuemei Li 2, Song Zhai 1, Xin Zhang 1, Xiaoli Jia 1 and Shuangsuo Dang 1,*
Round 1
Reviewer 1 Report
I think the results are encouraging for patients with viral Hepatitis B infection. The form of interferon used in this study achieve a level of cure not seen with current available treatments. I suggest to add a section and a Diagram which describe the interferon used. How it is made and a Diagram of the protein and how it differ from currently available forms.
1) A major shortcoming of this study is that the follow-up treatment or re-treatment as the Author call it, is only done with the Chinese made peg-IFNalpha -2b.
It definitely needed to be also done with the peg-IFNalpha which was used for the first treatment. I think the Authors need to include another group of patients who receive re-treatment with this Interferon.
Only then can the Authors say that Chinese made peg-IFNalpha 2b has statistically significant advantage.
2) I still think it is important to make clear to the reader how the two Interferons differ from each other. In the form of a diagram and if possible also SDS PAGE gels.
3) If anything is known about the mode of action for the different types of Interferon, please write this in Discussion. In what way does the mode of action for Interferon 2b variant differ from peg-IFNalpha.
Author Response
Dear editors and reviewers,
On behalf of my co-authors, we thank you very much for giving us an opportunity to revise our manuscript. We appreciated editor and reviewers very much for their positive and constructive comments and suggestions on our manuscript. These comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our study. We have studied comments carefully and have made corrections in red in the manuscript which we hope meet with approval.
The responds to the reviewer’s comments are as follows.
Reviewers' comments:
Comments and Suggestions for Authors#1：
I think the results are encouraging for patients with viral Hepatitis B infection. The form of interferon used in this study achieve a level of cure not seen with current available treatments. I suggest to add a section and a Diagram which describe the interferon used. How it is made and a Diagram of the protein and how it differ from currently available forms.
Point 1: A major shortcoming of this study is that the follow-up treatment or re-treatment as the Author call it, is only done with the Chinese made peg-IFNalpha -2b.It definitely needed to be also done with the peg-IFNalpha which was used for the first treatment. I think the Authors need to include another group of patients who receive re-treatment with this Interferon. Only then can the Authors say that Chinese made peg-IFNalpha 2b has statistically significant advantage.
Response 1: We appreciated your positive and constructive comments and suggestions very much. In the current study, we did not include a group of patients who received peg-IFN α-2a re-treatment due to the following reasons:
a）The Chinese-made peg-IFNα-2b used in this study was developed and produced by Xiamen Tebao Biological Engineering Co., Ltd and was marketed in China on October 15, 2016. It showed comparable efficacy and safety to the peg-IFN α-2a in its Phase III clinical trials and subsequent clinical use. Furthermore, Chinese-made peg-IFNα-2b is cheaper than peg-IFN α-2a. Most patients can afford peg-IFNα-2b treatment in China, an economically developing country. Thus, almost all patients with chronic HBV infection choose Chinese-made peg-IFNα-2b treatment since 2018. Besides, peg-IFN-α 2a (Pegasys®; Roche) was announced to withdraw from the Chinese market on September 16, 2022. As a result, it is difficult to include a group of patients who received peg-IFN α-2a re-treatment.
b) The main objective of this study was to demonstrate that most patients with HBsAg recurrence after being clinically cured by peg-IFN-α-based regimens can achieve functional cure again by peg-IFN-α re-treatment, rather than comparing the efficacy of peg-IFNα-2b and peg-IFNα-2a. In addition, several clinical studies have confirmed Chinese-made peg-IFNα-2b have comparable efficacy and safety to the peg-IFN α-2a. Thus, the lack of a group of patients receiving peg-IFN α-2a re-treatment did not influence the conclusions of this study.
Point 2: I still think it is important to make clear to the reader how the two Interferons differ from each other. In the form of a diagram and if it is possible also SDS PAGE gels.
Response 2: Both IFN-α-2a and IFN-α-2b are members of the IFN-α family. The main difference is that the 23rd amino acid of IFN-α-2a is lysine and the 23rd amino acid of IFN-α-2b is arginine. Peg-IFN α-2a (Pegasys®, U shape, 40 kD) is composed of an inert, branched, 40 kD U-shaped polyethylene glycol molecules attached to IFN-α-2a. Peg-IFN α-2b (PegBeron®, Y shape, 40 kD) is composed of an inert, branched, 40 kD Y-shaped polyethylene glycol molecules attached to IFN-α-2b. Compared with peg-IFNα-2a, peg-IFNα-2b has the same efficacy, but the structure is more stable and the immunogenicity is smaller, resulting in lower rate of neutralizing antibody production.
We have added the relevant content to the introduction section (Line 74-76).
Unfortunately, we failed to find the chemical structure diagram of Peg-IFNα-2a and Peg-IFNα-2b even though we carefully consulted the relevant literature.
Point 3: If anything is known about the mode of action for the different types of Interferon, please write this in Discussion. In what way does the mode of action for Interferon 2b variant differ from peg-IFN alpha.
Response 3: Both IFN-α-2a and IFN-α-2b are IFN-α subtypes. Peg-IFNα-2a and Peg-IFNα-2b share the same antiviral mechanism. They signal through a shared type I IFN heterodimeric receptor complex comprising two IFN-a receptor subunits (IFNAR1 and IFNAR2) that are present on nearly all nucleated cells. The IFN-IFNAR complex then activates the JAK-STAT pathway, resulting in the expression of dozens of interferon-simulating genes (ISGs), that function as downstream effectors to control viral replication and regulate immune responses. We have added the relevant content to the discussion section (Line 333-338).
Author Response File: 
Author Response.docx
Reviewer 2 Report
Wu and coworkers have undertaken a prospective observational study on the effects of peg-IFN alpha-2b in patients who experience recurrence of HBsAg after clinical cure with INF-alpha. This is a very important question to those in the HBV community. The lack of a control group is not ideal, and the study is small, but as a preliminary, proof of concept study, it's OK.
Major issues:
1) My main issue with this study is that there is no control group at all. If the study were larger, at the least the patients who refused treatment could be used as a control. Because of this, these findings must be considered to be preliminary. You should at least state in the manuscript the rate of spontaneous resolution of HBsAg, so the reader has some idea of how efficacious the drug treatment really is.
2) Table 1 shows the baseline characteristics. I was looking for evidence of actual HBV replication (rather than simply expression of HBsAg) and it says that 100% of patients were HBeAg negative, but 16% were HBeAg positive – there is clearly an error here!
3) I am entirely unsure what you mean by “clearance” vs “seroconversion”. My understanding is that they are the same thing. I did not see any explanation in the study as to the difference between these.
Minor issues:
1) I could not find the registration of this trial. Was it registered in China? If so, please give the study registration number in the text.
2) it is good practice to provide the drug name and manufacturer name, including city (line 91)
3) Please provide the statistics of the rate of seroconversion among patients who had previously received INF alpha 2-a vs 2-b. I know the numbers are so small it won’t be statistically meaningful, but it could provoke better studies in the future.
Author Response
Dear editors and reviewers,
On behalf of my co-authors, we thank you very much for giving us an opportunity to revise our manuscript. We appreciated editor and reviewers very much for their positive and constructive comments and suggestions on our manuscript. These comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our study. We have studied comments carefully and have made corrections in red in the manuscript which we hope meet with approval.
The responds to the reviewer’s comments are as follows.
Reviewers' comments:
Comments and Suggestions for Authors#2：
Wu and coworkers have undertaken a prospective observational study on the effects of peg-IFN alpha-2b in patients who experience recurrence of HBsAg after clinical cure with INF-alpha. This is a very important question to those in the HBV community. The lack of a control group is not ideal, and the study is small, but as a preliminary, proof of concept study, it's OK.
Major issues:
Point 1: My main issue with this study is that there is no control group at all. If the study were larger, at the least the patients who refused treatment could be used as a control. Because of this, these findings must be considered to be preliminary. You should at least state in the manuscript the rate of spontaneous resolution of HBsAg, so the reader has some idea of how efficacious the drug treatment really is.
Response 1: Thank you for your valuable suggestion. In the discussion section, I have added that the spontaneous HBsAg clearance rate is only 1 % -2.4 % per year. The details are as follows:
“Even so, we believe that enlarging the sample size or setting an un-treated control group will not change the conclusion of this study because the results of the current study already suggest a significantly higher rate of HBsAg clearance than the untreated spontaneous HBsAg clearance rate which is well known from many previous studies, that is, only1%–2.4% per year [28, 29].” We have added the relevant content to the discussion section. (Line 414-419)
Point 2: Table 1 shows the baseline characteristics. I was looking for evidence of actual HBV replication (rather than simply expression of HBsAg) and it says that 100% of patients were HBeAg negative, but 16% were HBeAg positive – there is clearly an error here!
Response 2: Thank you very much for your question. In view of your question that our data is wrong, I carefully check the original data in Table 1. Table 1 shows that 100% of patients were HBeAg negative, but 16% were HBeAb positive. Therefore, our data here is correct.
|
HBeAg negative, n (%) |
33(100.0) |
|
HBeAb positive, n (%) |
16(48.5) |
Point 3: I am entirely unsure what you mean by “clearance” vs “seroconversion”. My understanding is that they are the same thing. I did not see any explanation in the study as to the difference between these.
Response 3: HBsAg clearance is defined as HBsAg < 0.05 IU/mL. HBsAg seroconversion is defined as HBsAg < 0.05 IU/mL accompanied by HBsAb >10 mIU/mL. I have added relevant definitions to the Laboratory assessments section. (Line 117-119)
Minor issues:
Point 1: I could not find the registration of this trial. Was it registered in China? If so, please give the study registration number in the text.
Response 1: Yes, it was registered in China. The registration number is ChiCTR1900027154. (Line 85)
Point 2: it is good practice to provide the drug name and manufacturer name, including city (line 91)
Response 2: peg-IFN α-2b (PegBeron, subcutaneous injection, once weekly, Chinese-made, Xiamen, Xiamen Tebao Biological Engineering Co., Ltd) (Line 97-99)
Point 3: Please provide the statistics of the rate of seroconversion among patients who had previously received INF alpha 2-a vs 2-b. I know the numbers are so small it won’t be statistically meaningful, but it could provoke better studies in the future.
Response 3: Thank you for your valuable suggestion. We have added the relevant data to the introduction section according to your suggestion (Line 67-72). The details are as follows:
A total of 271 patients have achieved functional cure by peg-IFN α-based regimens in recent 7 years, including 48 patients treated with peg-IFN α-2a and 223 patients treated with peg-IFN α-2b. During a median of 110 weeks of follow-up, 35 patients experienced HBsAg recurrence [Rates of HBsAg recurrence for peg-IFN α-2a and peg-IFN α-2b treatment were 14.6% (7/48) and 12.6% (28/223), respectively].
Author Response File: Author Response.docx
