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Letter to the EditorHepatology Open Access | 10.1172/JCI161134

Concerns about the inverse relationship between baseline HBV DNA and on-treatment hepatocellular carcinoma risk

Shi Liu, Yongyin Li, and Jian Sun

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Find articles by Liu, S. in: JCI | PubMed | Google Scholar

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Find articles by Li, Y. in: JCI | PubMed | Google Scholar |

State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Find articles by Sun, J. in: JCI | PubMed | Google Scholar

Published August 1, 2022 - More info

Published in Volume 132, Issue 15 on August 1, 2022
J Clin Invest. 2022;132(15):e161134. https://doi.org/10.1172/JCI161134.
© 2022 Liu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 1, 2022 - Version history
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Concerns about the inverse relationship between baseline HBV DNA and on-treatment hepatocellular carcinoma risk. Reply.
Won-Mook Choi, Young-Suk Lim
Won-Mook Choi, Young-Suk Lim
Letter to the Editor Hepatology

Concerns about the inverse relationship between baseline HBV DNA and on-treatment hepatocellular carcinoma risk. Reply.

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Abstract

Authors

Won-Mook Choi, Young-Suk Lim

×

To the Editor:

We read with great interest the article by Choi et al., which concluded that baseline HBV DNA level was inversely associated with on-treatment hepatocellular carcinoma (HCC) risk in HBeAg-positive, noncirrhotic, chronic hepatitis B (CHB) patients (1). Their findings are novel, but several issues deserve discussion.

Firstly, the representativeness and potential selection bias for the study subjects are crucial, which will significantly influence the robustness and generalizability of study results. It’s uncertain whether the study subjects were enrolled consecutively, since only 2457 patients were included during the nearly ten-year enrollment at three centers. Independent cohorts with large sample size are needed to validate the conclusion.

Secondly, many confounders, like obesity, diabetes, drinking, and treatment response, were not adjusted in this study. Although the results were reproduced after excluding patients who did not achieve HBV DNA of less than 2000 IU/mL at year one, the effect of longitudinal virological response on HCC risk couldn’t be ignored. Besides, biochemical response, which has been shown to be associated with HCC risk (2), was also not adjusted.

Thirdly, it is widely accepted that high levels of HBV DNA were associated with increased HCC risk in the natural history cohort (3). However, this study showed opposite results in the nucleos(t)ide analogue–treated (NA-treated) cohort. We understand that HBeAg-positive patients in the immune-active phase, which are the target population of this study, are characterized by fluctuating but progressively decreasing HBV DNA levels, elevated alanine aminotransferase (ALT), and accumulated hepatic necroinflammation and fibrosis (4). It’s reasonable to speculate that lower baseline HBV DNA may indicate more advanced liver disease, which is a key risk factor for HCC. Although cirrhotic patients were excluded during enrollment and fibrosis 4 (FIB-4) index was adjusted in multivariate analysis, the disease severity of the enrolled patients in this study may still be heterogeneous, ranging from minimal to advanced liver damage. Without fully balancing the severity of liver damage, the inverse relationship between baseline HBV DNA level and on-treatment HCC risk might be an illusion.

Last but not least, the authors proposed that antiviral treatment can be initiated early in patients with high viral load regardless of ALT level for the prevention of HCC. However, there was no solid evidence to show the benefit of antiviral treatment in immune-tolerant patients. On the contrary, poor response to current treatments in those patients has been reported (5). Expanding current treatment indication without solid evidence would bring unnecessary potential side effects and the financial burden of long-term treatment for some patients.

Footnotes

Conflict of interest: JS consults for Guangzhou HEAS BioTech.

Address correspondence to: Jian Sun, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Phone: 86.20.62787432; Email: sunjian@smu.edu.cn.

Reference information: J Clin Invest. 2022;132(15):e161134. https://doi.org/10.1172/JCI161134.

See the related article at Increasing on-treatment hepatocellular carcinoma risk with decreasing baseline viral load in HBeAg-positive chronic hepatitis B .

See the related reply to the Letter to the Editor at Concerns about the inverse relationship between baseline HBV DNA and on-treatment hepatocellular carcinoma risk. Reply.

References
  1. Choi WM, et al. Increasing on-treatment hepatocellular carcinoma risk with decreasing baseline viral load in HBeAg-positive chronic hepatitis B. J Clin Invest. 2022;132(10):e154833.
    View this article via: JCI CrossRef PubMed Google Scholar
  2. Choi J, et al. Earlier alanine aminotransferase normalization during antiviral treatment is independently associated with lower risk of hepatocellular carcinoma in chronic hepatitis B. Am J Gastroenterol. 2020;115(3):406–414.
    View this article via: CrossRef PubMed Google Scholar
  3. Chen CJ, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295(1):65–73.
    View this article via: CrossRef PubMed Google Scholar
  4. Fattovich G, et al. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008;48(2):335–352.
    View this article via: CrossRef PubMed Google Scholar
  5. Chan HL, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA. Gastroenterology. 2014;146(5):1240–1248.
    View this article via: CrossRef PubMed Google Scholar
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