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Impact of alpha-fetoprotein on hepatocellular carcinoma development during entecavir treatment of chronic hepatitis B virus infection

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Entecavir (ETV) is one of the first-line nucleoside analogs for treating patients with chronic hepatitis B virus (HBV) infection. However, the hepatocellular carcinoma (HCC) risk for ETV-treated patients remains unclear.

Methods

A total of 496 Japanese patients with chronic HBV infection undergoing ETV treatment were enrolled in this study. The baseline characteristics were as follows: age 52.6 ± 12.0 years, males 58 %, positive for hepatitis B e antigen 45 %, cirrhosis 19 %, and median HBV DNA level 6.9 log copies (LC) per milliliter. The mean treatment duration was 49.9 ± 17.5 months.

Results

The proportions of HBV DNA negativity (below 2.6 LC/mL) were 68 % at 24 weeks and 86 % at 1 year, and the rates of alanine aminotransferase (ALT) level normalization were 62 and 72 %, respectively. The mean serum alpha-fetoprotein (AFP) levels decreased significantly at 24 weeks after ETV treatment initiation (from 29.0 ± 137.1 to 5.7 ± 27.9 ng/mL, p < 0.001). The cumulative incidence of HCC at 3, 5, and 7 years was 6.0, 9.6, and 17.2 %, respectively, among all enrolled patients. In a multivariate analysis, advanced age [55 years or older, hazard ratio (HR) 2.84; p = 0.018], cirrhosis (HR 5.59, p < 0.001), and a higher AFP level (10 ng/mL or greater) at 24 weeks (HR 2.38, p = 0.034) were independent risk factors for HCC incidence. HCC incidence was not affected by HBV DNA negativity or by ALT level normalization at 24 weeks.

Conclusions

The AFP level at 24 weeks after ETV treatment initiation can be the on-treatment predictive factor for HCC incidence among patients with chronic HBV infection.

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Abbreviations

AFP:

Alpha-fetoprotein

ALT:

Alanine aminotransferase

cccDNA:

Covalently closed circular DNA

ETV:

Entecavir

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

HCC:

Hepatocellular carcinoma

IFN:

Interferon

NA:

Nucleos(t)ide analog

ROC:

Receiver operating characteristic

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Acknowledgments

The authors thank Atsuo Inoue (Osaka General Medical Center), Masami Inada (Toyonaka Municipal Hospital), Ikuo Suzuki (Saiseikai Senri Hospital), Akira Takeda (Ashiya Municipal Hospital), Hiroyuki Ogawa (Nishinomiya Municipal Central Hospital), Mitsunari Yamamoto (Kinki Central Hospital of Mutual Aid Association of Public School Teachers, Itami, Hyogo, Japan), and Yukiko Saji (Itami City Hospital) for their support. This work was supported by a Grant-in-Aid for Research on Hepatitis from the Ministry of Health Labour and Welfare of Japan, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.

Conflict of interest

Professor Tetsuo Takehara received research grants from Merck Sharp and Dohme K.K. Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Bristol Myers Squibb.

The other authors have nothing to disclose.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Ryoko Yamada, Naoki Hiramatsu, Tsugiko Oze, Naoki Morishita, Naoki Harada, Takayuki Yakushijin, Takuya Miyagi, Yuichi Yoshida, Tomohide Tatsumi & Tetsuo Takehara

  2. Higashiosaka City Central Hospital, Higashiosaka, Osaka, Japan

    Sadaharu Iio

  3. Otemae Hospital, Osaka, Osaka, Japan

    Yoshinori Doi

  4. Sumitomo Hospital, Osaka, Osaka, Japan

    Akira Yamada

  5. NTT West Osaka Hospital, Osaka, Osaka, Japan

    Akira Kaneko

  6. Kansai Rosai Hospital, Amagasaki, Hyogo, Japan

    Hideki Hagiwara & Norio Hayashi

  7. National Hospital Organization Osaka National Hospital, Osaka, Osaka, Japan

    Eiji Mita

  8. Osaka Police Hospital, Osaka, Osaka, Japan

    Masahide Oshita

  9. Japan Community Health Care Organization Osaka Hospital, Osaka, Osaka, Japan

    Toshifumi Itoh

  10. Yao Municipal Hospital, Yao, Osaka, Japan

    Hiroyuki Fukui

  11. National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Osaka, Japan

    Taizo Hijioka

  12. Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Osaka, Japan

    Kazuhiro Katayama

  13. Minoh City Hospital, Minoh, Osaka, Japan

    Shinji Tamura

  14. Osaka Rosai Hospital, Sakai, Osaka, Japan

    Harumasa Yoshihara

  15. Ikeda Municipal Hospital, Ikeda, Osaka, Japan

    Yasuharu Imai

  16. National Hospital Organization Minami Wakayama Medical Center, Tanabe, Wakayama, Japan

    Michio Kato

  17. Department of General Medicine, Osaka University Hospital, Suita, Osaka, Japan

    Akinori Kasahara

  18. Department of Biomedical Statistics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Toshimitsu Hamasaki

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the Osaka Liver Forum

Corresponding author

Correspondence to Naoki Hiramatsu.

Additional information

R. Yamada and N. Hiramatsu contributed equally to this work and share first authorship.

Electronic supplementary material

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535_2014_1010_MOESM1_ESM.tif

Fig. S1 The change of AFP levels from the initiation of ETV treatment until 48 weeks after the initiation of ETV treatment, and from 24 weeks before HCC incidence until HCC incidence among patients who developed HCC. AFP levels at each time point are expressed as the mean ± standard error of the mean. (TIFF 26389 kb)

535_2014_1010_MOESM2_ESM.tif

Fig. S2 Cumulative HCC incidence among patients with undetectable HBV DNA at 24 weeks according to existing risk factors. a Patients of the low-risk group with a maximum of one risk factor (black solid line AFP level of 10 ng/mL or higher at 24 weeks, solid gray line cirrhosis, dashed black line 55 years or older) gray dashed line without any risk factor). b Patients of the high-risk group with more than two risk factors (solid black line AFP level of 10 ng/mL or higher at 24 weeks, 55 years or older, and cirrhosis, solid gray line AFP level of 10 ng/mL or higher at 24 weeks and cirrhosis, dashed black line AFP level of 10 ng/mL or higher at 24 weeks and 55 years or older, dashed gray line 55 years or older and cirrhosis). (TIFF 36806 kb)

535_2014_1010_MOESM3_ESM.tif

Fig. S3 Cumulative HCC incidence among patients with HBV infection according to VR at 24 weeks after ETV treatment initiation, stratified with the severity of liver disease (log-rank test). VR is defined as an HBV DNA level below 2.6 LC/mL. a Patients without cirrhosis. b Patients with cirrhosis. Black line no VR at 24 weeks, gray line VR at 24 weeks. (TIFF 36805 kb)

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Yamada, R., Hiramatsu, N., Oze, T. et al. Impact of alpha-fetoprotein on hepatocellular carcinoma development during entecavir treatment of chronic hepatitis B virus infection. J Gastroenterol 50, 785–794 (2015). https://doi.org/10.1007/s00535-014-1010-7

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  • DOI: https://doi.org/10.1007/s00535-014-1010-7

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