A Historical Overview on the Role of Hepatitis B and C Viruses as Aetiological Factors for Hepatocellular Carcinoma
Round 1
Reviewer 1 Report
A historical overview on the role of hepatitis B and C viruses as aetiological factors for hepatocellular carcinoma.
Stoffolini T and Stroffolini G
Cancers
Historical overviews of major cancer risk factors are always welcome. The current manuscript does a good job of covering some important points about HBV and HCV and their relationship to HCC. I think, however, that some additional references would be helpful. It would also be beneficial to take a look at some of the references (please see below) to make sure they are probably quoted. As there are some grammatical errors, I would suggest that the authors read over the manuscript carefully.
Specific suggestions:
Line 35: The estimate of the percentage of liver cancers that are HCC is thought to be 75-80%, rather than 90%. Please see most recent publication using IARC data: Rumgay H et al., Eur J Cancer 2022;161:108-118.
Lines 47-65: As the manuscript is an historical overview, it is curious that no mention is made of Baruch S. Blumberg, the scientist who identified HBV, then developed a diagnostic test and the original vaccine. He won a Nobel Prize for this work.
Line 65: In the line that ends with ‘…and no cases have occurred since 1995’, please specify where this refers to cases of HBV infection or cases of HCC.
Line 73: In the definition of additive interaction, it is not clear what is mean by ‘minus 1’ at the end of the sentence. Is this a typo?
Lines 79-80: Table 1 shown here does not show the HBsAg(+) vs anti-HCV(+). This table is the same as Table 2.
Line 101: There is a few typos in this sentence. I believe the sentence should read ‘…>60 gr/day increases nearly two-fold…’
Line 116: The HR and 95%CI shown here from the Sohn study are not the correct ones. The HR and 95%CI quoted are for all liver-related mortality among persons who were anti-HBc(+) and had a high APRI score.
Line 129: Please explain what is meant by ‘One of the key passages…’
Line 142: Please define ‘cases’ in this sentence. Is the intent to say ‘HBV infections’?
Lines 151-152: Please provide references for the statement that the HBV vaccine in some countries is not offered free of charge and is in low supply.
Lines 155-162 The statement about avoidance of sharing needles/syringes among IDUs is questionable as a means of preventing HBV-related HCC. Although IDUs may get exposed to HBV, the great majority of adults will not develop a chronic infection, thus would not be at increased risk of HBV-related HCC. If, alternatively, the authors have references to suggest that IDUs are at increased risk of HBV-related HCC, they should include the references here.
Line 159: As noted above, the reference #28 is a study of acute HBV infection among adults in the U.S. As the focus of this manuscript is on HCC, studies of acute HBV infection among adults are not relevant to understanding the etiology of HCC.
Line 160-162: This statement is a little misleading. What reference #29 reported was that among persons who reported ever use of injectable drugs, the percent who were anti-HBc (+) increased from 35.3% in 2001-2006 to 58.4% in 2013-2018. The difference in these prevalences was not statistically significant, and the numbers of persons in each year-grouping were small. In addition, there was no indication that IV drug use was the sole source of exposure. Finally, as anti-HBc doesn’t distinguish current and resolved HBV, the relevance to risk of HCC is highly questionable.
Line 163: Please explain what is meant by the parenthetical phrase: (for subject that are not susceptible to HBV). As the following two paragraphs are about suppressing HBV replication, is the intent of the parenthetical statement to say (for persons with chronic HBV infections)?
Line 231: Please provide a reference to support the statement that there is synergism between HCV and alcohol consumption on risk of HCC.
Line 249: Please explain the adjusted OR and 95%CI that are displayed at the end of the sentence.
Line 250: As with the comment about in regard to HBV, it would be better for the parenthetical phrase to say (for persons who are infected with HCV).
Line 254-255: Is the intent of this sentence to say that only 20.5% of persons with cirrhosis and HCV have received HBV vaccine?
Line 269: Please clarify ‘Since the half of the 2010’s…’
Line 286: The sentence that states, ‘HBV dominates in Africa…’ should be altered to read that ‘HBV dominates in sub-Saharan Africa’. HCV is a bigger factor in northern Africa. Please note that this statement should also be changed in the Abstract.
Line 303-308: The wording describing MAFLD isn’t quite right. MAFLD is defined as having hepatic steatosis and any 3 of the following: overweight/obesity, diabetes mellitus, metabolic dysregulation. Persons who are HBV(+) or HCV(+) or who have alcoholic liver disease can also have MAFLD. On the other hand, NAFLD was generally defined as having fatty liver disease in the absence of known causes such as alcohol, HBV or HCV. Thus, if one is looking at different risk factors, it would be preferable to examine NAFLD rather than MAFLD.
Line 344: As with the comment above, it is NAFLD, rather than MAFLD, that is likely to be the leading cause of HCC in the future.
Author Response
W thank the reviewer for its very careful and valuable evaluation, that adds value to our work.
Author Response File: 
Author Response.docx
Reviewer 2 Report
auses of hepatocarcinogenesis.
Overall very well written, but I think it would be better to change one point.
Diabetes is cited as a factor involved in carcinogenesis by HBV. However, weight control is listed as secondary prevention in Table 3. I think that appropriate diet therapy and exercise therapy, which are the principles of diabetes treatment, should be specifically described here.
Author Response
We thank the reviewer for its very careful and valuable evaluation, that adds value to our work.
Author Response File: Author Response.docx
