Advertisement

Clinical and Experimental Medicine

, Volume 19, Issue 3, pp 309–320 | Cite as

Changes in APRI and FIB-4 in HBeAg-negative treatment-naive chronic hepatitis B patients with significant liver histological lesions receiving 5-year entecavir therapy

  • Ruyu LiuEmail author
  • Jiang Guo
  • Yao Lu
  • Lu Zhang
  • Ge Shen
  • Shuling Wu
  • Mi Chang
  • Leiping Hu
  • Hongxiao Hao
  • Minghui Li
  • Yao Xie
Original Article
  • 70 Downloads

Abstract

According to guidelines, antiviral therapy for adults with immune-active chronic hepatitis B (CHB) should be adopted to decrease the risk of liver-related complications. Fibrosis assessment during antiviral treatment is a key step in antiviral therapy evaluation. Liver biopsy is the gold standard for assessing the degree of liver necroinflammation and fibrosis. However, because of its cost and the risk of life-threatening complications, performing a liver biopsy more than once after long-term effective treatment is difficult. In this study, we aimed to evaluate changes in liver fibrosis during 5 years of entecavir (ETV) treatment using noninvasive fibrosis markers in hepatitis B e-antigen (HBeAg)-negative treatment-naive CHB patients who require antiviral therapy. A total of 303 HBeAg-negative treatment-naive patients were enrolled in this study. Liver biopsy was performed before initiation of antiviral therapy. The diagnosis of CHB was made according to Chinese guidelines for the management of CHB. Patients requiring antiviral therapy (liver fibrosis stage ≥ F2, METAVIR scoring system) were treated with ETV for at least 5 years. These patients were followed up at 6-month intervals. A clinical and virological evaluation was performed at baseline and again at 12, 24, 36, 48, and 60 months during ETV treatment. Aspartate Aminotransferase to Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) index were used to assess dynamic changes in liver fibrosis in HBeAg-negative CHB patients after 1, 2, 3, 4, and 5 years of ETV treatment. All enrolled patients underwent liver biopsy at baseline. Using the METAVIR fibrosis stages, there were 107, 125, 54, and 17 patients in F1, F2, F3, and F4 stages, respectively. The APRI and FIB-4 indexes enabled the correct identification of patients with severe fibrosis (METAVIR F3–F4), with an area under the receiver operating characteristic curve of 0.77 (95% confidence interval [CI] 0.72–0.83) and 0.76 (95% CI 0.70–0.82), respectively. The APRI values decreased significantly in F2 and F3 patients after 1 year of ETV therapy (P < 0.01). However, for F4 patients, APRI values decreased significantly at year 3 (P < 0.05). The FIB-4 values of F2, F3, and F4 patients who received ETV treatment were significantly decreased after 1, 3, and 5 years of ETV therapy, respectively (P < 0.05). APRI and FIB-4 values decreased significantly during 5-year ETV treatment in HBeAg-negative CHB patients, indicating that these noninvasive fibrosis tests might be useful for monitoring improvement in liver fibrosis and assessing treatment efficacy during long-term ETV treatment.

Keywords

Hepatitis B virus Chronic hepatitis B Liver fibrosis Entecavir APRI FIB-4 

Notes

Funding

This study was supported by Beijing Municipal Administration of Hospitals Incubating Program (PX2018060), Youth Programme from Beijing Municipal Administration of Hospitals (QML20181803), and Seedling Cultivation Programme of Beijing Ditan Hospital (DTYM201609).

Conflict of interest

The authors declare no competing financial interests.

Ethical approval and informed consent

All patients signed the informed consent before liver biopsy, and all clinical procedures were in accordance with the Declaration of Helsinki in 1983. The study protocol was permitted by the Institutional Review Board of Beijing Ditan Hospital.

References

  1. 1.
    Polaris Observatory C. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. The Lancet: Gastroenterol Hepatol. 2018;3(6):383–403.Google Scholar
  2. 2.
    Shin SK, Kim JH, Park H, et al. Improvement of liver function and non-invasive fibrosis markers in hepatitis B virus-associated cirrhosis: 2 years of entecavir treatment. J Gastroenterol Hepatol. 2015;30(12):1775–81.CrossRefGoogle Scholar
  3. 3.
    Wang J, Shen T, Huang X, et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol. 2016;65(4):700–10.CrossRefGoogle Scholar
  4. 4.
    Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130(3):678–86.CrossRefGoogle Scholar
  5. 5.
    Fattovich G, Brollo L, Giustina G, et al. Natural history and prognostic factors for chronic hepatitis type B. Gut. 1991;32(3):294–8.CrossRefGoogle Scholar
  6. 6.
    Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295(1):65–73.CrossRefGoogle Scholar
  7. 7.
    Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351(15):1521–31.CrossRefGoogle Scholar
  8. 8.
    Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348(9):800–7.CrossRefGoogle Scholar
  9. 9.
    Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99.CrossRefGoogle Scholar
  10. 10.
    European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.CrossRefGoogle Scholar
  11. 11.
    Mohamadnejad M, Tavangar SM, Sotoudeh M, et al. Histopathological Study of Chronic Hepatitis B: a Comparative Study of Ishak and METAVIR Scoring Systems. Int J Organ Transpl Med. 2010;1(4):171–6.Google Scholar
  12. 12.
    WHO. Guidelines for the prevention, care and treatment of persons with Chronic Hepatitis B infection. Geneva: WHO; 2015.Google Scholar
  13. 13.
    Mallet V, Dhalluin-Venier V, Roussin C, et al. The accuracy of the FIB-4 index for the diagnosis of mild fibrosis in chronic hepatitis B. Aliment Pharmacol Ther. 2009;29(4):409–15.CrossRefGoogle Scholar
  14. 14.
    Kim BK, Kim DY, Park JY, et al. Validation of FIB-4 and comparison with other simple noninvasive indices for predicting liver fibrosis and cirrhosis in hepatitis B virus-infected patients. Liver Int. 2010;30(4):546–53.CrossRefGoogle Scholar
  15. 15.
    European Association for Study of L, Asociacion Latinoamericana para el Estudio del H. EASL-ALEH Clinical Practice Guidelines: non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63(1):237–64.CrossRefGoogle Scholar
  16. 16.
    Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24(2):289–93.CrossRefGoogle Scholar
  17. 17.
    Li Q, Chen L, Zhou Y. Changes of FibroScan, APRI, and FIB-4 in chronic hepatitis B patients with significant liver histological changes receiving 3-year entecavir therapy. Clin Exp Med. 2018;18(2):273–82.CrossRefGoogle Scholar
  18. 18.
    Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468–75.CrossRefGoogle Scholar
  19. 19.
    Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. J Hepatol. 2012;56(5):1171–80.CrossRefGoogle Scholar
  20. 20.
    Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124(1):105–17.CrossRefGoogle Scholar
  21. 21.
    Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131(6):1743–51.CrossRefGoogle Scholar
  22. 22.
    Enomoto M, Mori M, Ogawa T, et al. Usefulness of transient elastography for assessment of liver fibrosis in chronic hepatitis B: regression of liver stiffness during entecavir therapy. Hepatol Res. 2010;40(9):853–61.CrossRefGoogle Scholar
  23. 23.
    Wong GL, Wong VW, Choi PC, et al. On-treatment monitoring of liver fibrosis with transient elastography in chronic hepatitis B patients. Antivir Ther. 2011;16(2):165–72.CrossRefGoogle Scholar
  24. 24.
    Kim MN, Kim SU, Park JY, et al. Risk assessment of liver-related events using transient elastography in patients with chronic hepatitis B receiving entecavir. J Clin Gastroenterol. 2014;48(3):272–8.CrossRefGoogle Scholar
  25. 25.
    Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection: comparison with liver biopsy and fibrotest. Hepatology. 2007;46(1):32–6.CrossRefGoogle Scholar
  26. 26.
    Arends P, Sonneveld MJ, Zoutendijk R, et al. Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians. Gut. 2015;64(8):1289–95.CrossRefGoogle Scholar
  27. 27.
    Suzuki F, Hosaka T, Suzuki Y, et al. Long-term outcome of entecavir treatment of nucleos(t)ide analogue-naive chronic hepatitis B patients in Japan. J Gastroenterol. 2019;54:182–93.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Liver Diseases Center, Beijing Ditan HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.Tumor Interventional Department, Beijing Ditan HospitalCapital Medical UniversityChaoyang District, BeijingPeople’s Republic of China

Personalised recommendations