HCV Genotype Has No Influence on the Incidence of Diabetes—EpiTer Multicentre Study

Round 1

Reviewer 1 Report

The work is interesting, as the topic is very hot. It is methodologically quite correct. The tables are clear.

However, the authors have omitted to refer both in the introduction and above all in discussion to several recent studies that give strength and support their conclusions. Therefore, several issues have to be addressed.

1- In Introduction, the authors state “Chronic hepatitis C virus is … one of the most often occurring reasons of liver cirrhosis and hepatocellular carcinoma (HCC) contributing”. Recently it was observed a different HCC occurrence in HCV patients treated with different direct acting antivirals (J Transl Med. 2019 Aug 28;17(1):292. doi: 10.1186/s12967-019-2033-x.). This issue should be added in introduction.

2- In Conclusions, the authors state “It seems that the elimination of HCV may contribute to the reduction of the incidence of diabetes, too.”. But they cited only a few studies that simply observed that eliminating the C virus infection reduces insulin resistance. Originally, a recent study have shown that the reduction of IR through the pharmacological eradication of HCV by direct-acting antivirals leads to a reduction in the onset of type 2 diabetes (Diabetes, Obesity and Metabolism, 2020, 22(12):2408–2416. doi: 10.1111/dom.14168). The above study supports the above conclusion that the authors only speculated.

3- At the end of the discussion the authors state “HCV infection has been treated in the last years as a liver metabolic disease which may also be a risk factor of arteriosclerosis and cardiovascular diseases –coronary artery disease, a stroke, and peripheral vascular disease.”. Notably, in the last year, some studies have shown that the reduction of IR through the pharmacological eradication of HCV by direct-acting antivirals leads to both a reduction of clinical expressions of atherosclerosis both in general polulation (Atherosclerosis, 2020, 296:40–47. doi: 10.1016/j.atherosclerosis.2020.01.010) and in prediabetic subjects (Nutrition, Metabolism & Cardiovascular Diseases (2021) 31, 2345e2353. doi: 10.1016/j.numecd.2021.04.016). These issues as well as the above references deserve to be commented in discussion by the authors.

4- Chronic hepatopathy and IR are bidirectionally correlated and, consequently, the development of pre-diabetes and diabetes is the most direct consequence at the extrahepatic level. Very recent reviews explain in an updated and complete way the pathophysiological mechanisms that support this relationship (Antioxidants, 2021, 10(2), pp. 1–25, 270. doi: 10.3390/antiox10020270. - Processes, 2021, 9(1), pp. 1–18, 135. doi: 10.3390/pr9010135), and also the correlation between chronic liver damage and CV risk (Rev Cardiovasc Med. 2021 Sep 24;22(3):755-768. doi: 10.31083/j.rcm2203082). Authors should add the above references to the manuscript.

5- Notably, a recent study performed using liver biopsy in type 2 diabetes mellitus showed that steatohepatitis represents the sole feature of liver damage in type 2 diabetes. (PLoS One. 2017 Jun 1;12(6):e0178473. doi: 10.1371/journal.pone.0178473.). This observation suggests a rapid evolution of liver damage in the diabetic subject. This issue and above reference should be added and commented on in the text.

6- In the text there are some typos.

7- The manuscript requires linguistic revision by a native English speaker.

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

The authors aim to study the HCV infection in relation to the prevalence of diabetes mellitus. To evaluate the overall incidence of diabetes in HCV patients, the authors conducted a study comprising of 2898 patients with chronic HCV, which is by far more a good population number to examine. The study is well organized and indicates an interesting observation. However, There are few concerns as stated below:

 

1. The authors studied the patients with HCV infection in regards to diabetes and with no diabetes; however, another proper control could be with healthy population as well.

 

2. On page 2, second paragraph of introduction, change the word ‘infecting’ to infections.

 

3. Discussion is lacking proper references. For example, on page 4, paragraph 1,2 and 3 are without proper references.

 

4. On page 5, second paragraph, change the word ‘persons’ to people and in last line of same paragraph, change the word ‘at’ to in.

 

5. On page 5, 5^th paragraph, third line, please edit the line. In the next line, please change to ‘one also observes’ in place of one observes also.

 

6. On page 6, paragraph 3,4 and 5 are missing references.

Last paragraph on same page, edit the statement to correct grammar.

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

The manuscript is well written and valid both in the  results presentation  and in their  interpretation.the patient sample is big enough to allow a statistical validation so that  presented conclusions seem  quite  convincing. 

The authors  state in the  discussion  that the metabolic aspects contribute to the progression  of fibrosis, cirrhosis and hepatocellular  carcinoma, they should specify that  this,in turn, may contribute to a worse response  to antivirals by the development of RAS (Resistance associate mutations in HCV patients failing DAA treatment. New Microbiol 44,1 2021;12-18).

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The authors warmly welcomed the suggestions of this reviewer.
However, while agreeing with all the observations made by this reviewer, they did not include some suggested references in the manuscript, in particular those indicated in points 2, 3 and 4.
Therefore, although the revised document appears to have improved, this reviewer suggests adding missing suggested references in the text.

Author Response

Thank you very much. According to the reviewer's suggestion, I previously added a very interesting suggestion from point 2 to the discussion and, on the basis of this, I changed the conclusions from "seems to be" to "is" and it is worth adding in the conclusions that I have not changed, that the elimination of HCV reduces insulin resistance - of course I will refer to this in the text again. I allowed myself to refer to point 3 quite briefly, because the impact of HCV eradication on cardiovascular events based on our EpiTer study is the subject of another work that is currently being reviewed. Of course, I agree with it the most - I referred to it on page 7, reference 43. Rozserze is an issue at work, but slightly because it is not the main topic, but with the emphasis that, among other things (there are many mechanisms) by reducing insulin resistance and diabetes mellitus contributes to the reduction of atherosclerosis and cardiovascular disease. Of course, the pathophysiological pathways of the development of insulin resistance and diabetes in chronic liver diseases are complex, especially if there are several etilologies, e.g. obesity, metabolic syndrome or viral infections such as HCV - as I mentioned in the paper - from pages 4 to 7, especially 6 and 7, taking into account items 44-46 of the suggested literature. But as suggested, it will extend even more thoroughly. Thank you very much for valuable and correct comments.

 

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.