Risk factors of hepatocellular carcinoma in hepatitis B surface antigen seroclearance patients: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

JIA Rongrong ¹ , HUO Rongrui ^2,3 , LUO Chengpiao ¹ , ZHONG Jianhong ² , GUO Dexiang ² ,  ZHANG Chunyan ¹

1. Experimental Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, P.R.China;
2. Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, P.R.China;
3. Editorial Department, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, P.R.China;

Corresponding?author：

ZHANG Chunyan, Email: zcy_263@163.com

Keywords：

Chronic Hepatitis B; Hepatocellular carcinoma; Hepatitis B Surface Antigen Seroclearance; Liver cirrhosis; Meta-analysis; Systematic review

DOI：

10.7507/1672-2531.201810094

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ObjectivesTo systematically review the risk factors of hepatocellular carcinoma (HCC) in patients with hepatic B surface antigen (HBsAg).MethodsScopus, EMbase, PubMed, and The Cochrane Library databases were systematically searched for relevant studies on HCC after HBsAg seroclearance from inception to October 31^st, 2017. Two reviewers independently screened literature, extracted the data, and evaluated the risk of bias in the included studies. Meta-analysis was then conducted using R 3.5.3 software.ResultsA total of 28 studies involving 105 411 patients were included. Among 105 411 patients with chronic hepatitis B (CHB), 7 656 patients occurred spontaneously HBsAg seroclearance, while 1 248 patients had HBsAg seroclearance after interferon or nucleoside analogue therapy. The rate of HBsAg seroclearance was 6.77%. Meta-analysis showed that risk factors for HCC after serum HBsAg conversion included cirrhosis (OR=6.43, 95%CI 3.56 to 11.60, P<0.001), male (OR=2.72, 95%CI 1.66 to 4.46,P<0.001), and age ≥50 years at HBsAg seroclearance (OR=3.71, 95%CI 2.17 to 6.35,P<0.001).ConclusionsPatients with CHB after HBsAg seroclearance are still at risk of developing HCC. Therefore, periodic surveillance is recommended, especially for male patients, patients with cirrhosis, and patients who experience HBsAg seroclearance when over 50.

Citation： JIA Rongrong, HUO Rongrui, LUO Chengpiao, ZHONG Jianhong, GUO Dexiang, ZHANG Chunyan. Risk factors of hepatocellular carcinoma in hepatitis B surface antigen seroclearance patients: a systematic review. Chinese Journal of Evidence-Based Medicine, 2018, 18(12): 1311-1317. doi: 10.7507/1672-2531.201810094 Copy

1.	Burns GS, Thompson AJ. Viral hepatitis B: clinical and epidemiological characteristics. Cold Spring Harb Perspect Med, 2014, 4(12): a024935.
2.	Liu J, Yang HI, Lee MH, et al. Distinct seromarkers predict different milestones of chronic hepatitis B progression. Hepatology, 2014, 60(1): 77-86.
3.	Manno M, Camma C, Schepis F, et al. Natural history of chronic HBV carriers in northern Italy: morbidity and mortality after 30 years. Gastroenterology, 2004, 127(3): 756-763.
4.	Liu F, Wang XW, Chen L, et al. Systematic review with meta-analysis: development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis B surface antigen seroclearance. Aliment Pharmacol Ther, 2016, 43(12): 1253-1261.
5.	Zhao C, Ma YL, Li LQ, et al. Letter: clinical outcomes of HBsAg loss in chronic HBV infection. Aliment Pharmacol Ther, 2016, 44(5): 535-536.
6.	Zhang XY, Jia RR, Xiang X, et al. Letter: older age and male gender increase the risk of hepatocellular carcinoma after hepatitis B surface antigen (HBsAg) seroclearance. Aliment Pharmacol Ther, 2017, 46(9): 906-908.
7.	Yuen MF, Wong DK, Fung J, et al. HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology, 2008, 135(4): 1192-1199.
8.	Tong MJ, Nguyen MO, Tong LT, et al. Development of hepatocellular carcinoma after seroclearance of hepatitis B surface antigen. Clin Gastroenterol Hepatol, 2009, 7(8): 889-893.
9.	Ahn SH, Park YN, Park JY, et al. Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. J Hepatol, 2005, 42(2): 188-194.
10.	Arase Y, Ikeda K, Suzuki F, et al. Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B. Am J Med, 2006, 119(1): 71.
11.	Kim JH, Lee YS, Lee HJ, et al. HBsAg seroclearance in chronic hepatitis B: implications for hepatocellular carcinoma. J Clin Gastroenterol, 2011, 45(1): 64-68.
12.	Huo TI, Wu JC, Lee PC, et al. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis. Hepatology, 1998, 28(1): 231-236.
13.	Chen YC, Sheen IS, Chu CM, et al. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology, 2002, 123(4): 1084-1089.
14.	Idilman R, Cinar K, Seven G, et al. Hepatitis B surface antigen seroconversion is associated with favourable long-term clinical outcomes during lamivudine treatment in HBeAg-negative chronic hepatitis B patients. J Viral Hepat, 2012, 19(3): 220-226.
15.	Da Silva LC, Madruga CL, Carrilho FJ, et al. Spontaneous hepatitis B surface antigen clearance in a long-term follow-up study of patients with chronic type B hepatitis. Lack of correlation with hepatitis C and D virus superinfection. J Gastroenterol, 1996, 31(5): 696-701.
16.	Fattovich G, Giustina G, Sanchez-Tapias J, et al. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J Gastroenterol, 1998, 93(6): 896-900.
17.	De Franchis R, Meucci G, Vecchi M, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med, 1993, 118(3): 191-194.
18.	Nam SW, Jung JJ, Bae SH, et al. Clinical outcomes of delayed clearance of serum HBsAG in patients with chronic HBV infection. Korean J Intern Med, 2007, 22(2): 73-76.
19.	Simonetti J, Bulkow L, Mcmahon BJ, et al. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. Hepatology, 2010, 51(5): 1531-1537.
20.	Cho JY, Paik YH, Sohn W, et al. Patients with chronic hepatitis B treated with oral antiviral therapy retain a higher risk for HCC compared with patients with inactive stage disease. Gut, 2014, 63(12): 1943-1950.
21.	Chen YC, Jeng WJ, Chien RN, et al. Clinical outcomes after spontaneous and nucleos(t)ide analogue-treated HBsAg seroclearance in chronic HBV infection. Aliment Pharmacol Ther, 2016, 43(12): 1311-1318.
22.	Kim GA, Lee HC, Kim MJ, et al. Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance. J Hepatol, 2015, 62(5): 1092-1099.
23.	Mcmahon BJ, Holck P, Bulkow L, et al. Serologic and clinical outcomes of 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med, 2001, 135(9): 759-768.
24.	Lauret E, Gonzalez-Dieguez ML, Rodriguez M, et al. Long-term outcome in Caucasian patients with chronic hepatitis B virus infection after HBsAg seroclearance. Liver Int, 2015, 35(1): 140-147.
25.	Gounder PP, Bulkow LR, Snowball M, et al. Nested case-control study: hepatocellular carcinoma risk after hepatitis B surface antigen seroclearance. Aliment Pharmacol Ther, 2016, 43(11): 1197-1207.
26.	Ferreira SC, Chacha SG, Souza FF, et al. Factors associated with spontaneous HBsAg clearance in chronic hepatitis B patients followed at a university hospital. Ann Hepatol, 2014, 13(6): 762-770.
27.	Moucari R, Korevaar A, Lada O, et al. High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study. J Hepatol, 2009, 50(6): 1084-1092.
28.	Lim TH, Gane E, Moyes C, et al. Serological and clinical outcomes of horizontally transmitted chronic hepatitis B infection in New Zealand Maori: results from a 28-year follow-up study. Gut, 2015, 64(6): 966-972.
29.	Tseng TC, Liu CJ, Chen CL, et al. Higher lifetime chance of spontaneous surface antigen loss in hepatitis B carriers with genotype C infection. Aliment Pharmacol Ther, 2015, 41(10): 949-960.
30.	Kim JH, Lee JH, Park SJ, et al. Factors associated with natural seroclearance of hepatitis B surface antigen and prognosis after seroclearance: a prospective follow-up study. Hepatogastroenterology, 2008, 55(82-83): 578-581.
31.	Yip TC, Chan HL, Wong VW, et al. Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J Hepatol, 2017, 67(5): 902-908.
32.	Liu J, Yang HI, Lee MH, et al. Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma. Gut, 2014, 63(10): 1648-1657.
33.	Park YM, Lee SG. Clinical features of HBsAg seroclearance in hepatitis B virus carriers in South Korea: a retrospective longitudinal study. World J Gastroenterol, 2016, 22(44): 9836-9843.
34.	Orito E, Hasebe C, Kurosaki M, et al. Risk of hepatocellular carcinoma in cirrhotic hepatitis B virus patients during nucleoside/nucleotide analog therapy. Hepatol Res, 2015, 45(8): 872-879.
35.	Fwu CW, Chien YC, Kirk GD, et al. Hepatitis B virus infection and hepatocellular carcinoma among parous Taiwanese women: nationwide cohort study. J Natl Cancer Inst, 2009, 101(14): 1019-1027.
36.	Qu LS, Liu JX, Zhang HF, et al. Effect of serum hepatitis B surface antigen levels on predicting the clinical outcomes of chronic hepatitis B infection: A meta-analysis. Hepatol Res, 2015, 45(9): 1004-1013.
37.	Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int, 2016, 10(1): 1-98.
38.	Lok AS, Mcmahon BJ. Chronic hepatitis B: update 2009. Hepatology, 2009, 50(3): 661-662.
39.	Yuen MF, Wong DK, Sablon E, et al. HBsAg seroclearance in chronic hepatitis B in the Chinese: virological, histological, and clinical aspects. Hepatology, 2004, 39(6): 1694-1701.
40.	Seto WK, Tanaka Y, Wong DK, et al. Longitudinal profiles of highly sensitive hepatitis B surface antigen levels: re-evaluation of HBsAg seroclearance. Liver Int, 2016, 36(5): 642-650.

1. Burns GS, Thompson AJ. Viral hepatitis B: clinical and epidemiological characteristics. Cold Spring Harb Perspect Med, 2014, 4(12): a024935.
2. Liu J, Yang HI, Lee MH, et al. Distinct seromarkers predict different milestones of chronic hepatitis B progression. Hepatology, 2014, 60(1): 77-86.
3. Manno M, Camma C, Schepis F, et al. Natural history of chronic HBV carriers in northern Italy: morbidity and mortality after 30 years. Gastroenterology, 2004, 127(3): 756-763.
4. Liu F, Wang XW, Chen L, et al. Systematic review with meta-analysis: development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis B surface antigen seroclearance. Aliment Pharmacol Ther, 2016, 43(12): 1253-1261.
5. Zhao C, Ma YL, Li LQ, et al. Letter: clinical outcomes of HBsAg loss in chronic HBV infection. Aliment Pharmacol Ther, 2016, 44(5): 535-536.
6. Zhang XY, Jia RR, Xiang X, et al. Letter: older age and male gender increase the risk of hepatocellular carcinoma after hepatitis B surface antigen (HBsAg) seroclearance. Aliment Pharmacol Ther, 2017, 46(9): 906-908.
7. Yuen MF, Wong DK, Fung J, et al. HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology, 2008, 135(4): 1192-1199.
8. Tong MJ, Nguyen MO, Tong LT, et al. Development of hepatocellular carcinoma after seroclearance of hepatitis B surface antigen. Clin Gastroenterol Hepatol, 2009, 7(8): 889-893.
9. Ahn SH, Park YN, Park JY, et al. Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. J Hepatol, 2005, 42(2): 188-194.
10. Arase Y, Ikeda K, Suzuki F, et al. Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B. Am J Med, 2006, 119(1): 71.
11. Kim JH, Lee YS, Lee HJ, et al. HBsAg seroclearance in chronic hepatitis B: implications for hepatocellular carcinoma. J Clin Gastroenterol, 2011, 45(1): 64-68.
12. Huo TI, Wu JC, Lee PC, et al. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis. Hepatology, 1998, 28(1): 231-236.
13. Chen YC, Sheen IS, Chu CM, et al. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection. Gastroenterology, 2002, 123(4): 1084-1089.
14. Idilman R, Cinar K, Seven G, et al. Hepatitis B surface antigen seroconversion is associated with favourable long-term clinical outcomes during lamivudine treatment in HBeAg-negative chronic hepatitis B patients. J Viral Hepat, 2012, 19(3): 220-226.
15. Da Silva LC, Madruga CL, Carrilho FJ, et al. Spontaneous hepatitis B surface antigen clearance in a long-term follow-up study of patients with chronic type B hepatitis. Lack of correlation with hepatitis C and D virus superinfection. J Gastroenterol, 1996, 31(5): 696-701.
16. Fattovich G, Giustina G, Sanchez-Tapias J, et al. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J Gastroenterol, 1998, 93(6): 896-900.
17. De Franchis R, Meucci G, Vecchi M, et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med, 1993, 118(3): 191-194.
18. Nam SW, Jung JJ, Bae SH, et al. Clinical outcomes of delayed clearance of serum HBsAG in patients with chronic HBV infection. Korean J Intern Med, 2007, 22(2): 73-76.
19. Simonetti J, Bulkow L, Mcmahon BJ, et al. Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. Hepatology, 2010, 51(5): 1531-1537.
20. Cho JY, Paik YH, Sohn W, et al. Patients with chronic hepatitis B treated with oral antiviral therapy retain a higher risk for HCC compared with patients with inactive stage disease. Gut, 2014, 63(12): 1943-1950.
21. Chen YC, Jeng WJ, Chien RN, et al. Clinical outcomes after spontaneous and nucleos(t)ide analogue-treated HBsAg seroclearance in chronic HBV infection. Aliment Pharmacol Ther, 2016, 43(12): 1311-1318.
22. Kim GA, Lee HC, Kim MJ, et al. Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance. J Hepatol, 2015, 62(5): 1092-1099.
23. Mcmahon BJ, Holck P, Bulkow L, et al. Serologic and clinical outcomes of 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med, 2001, 135(9): 759-768.
24. Lauret E, Gonzalez-Dieguez ML, Rodriguez M, et al. Long-term outcome in Caucasian patients with chronic hepatitis B virus infection after HBsAg seroclearance. Liver Int, 2015, 35(1): 140-147.
25. Gounder PP, Bulkow LR, Snowball M, et al. Nested case-control study: hepatocellular carcinoma risk after hepatitis B surface antigen seroclearance. Aliment Pharmacol Ther, 2016, 43(11): 1197-1207.
26. Ferreira SC, Chacha SG, Souza FF, et al. Factors associated with spontaneous HBsAg clearance in chronic hepatitis B patients followed at a university hospital. Ann Hepatol, 2014, 13(6): 762-770.
27. Moucari R, Korevaar A, Lada O, et al. High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study. J Hepatol, 2009, 50(6): 1084-1092.
28. Lim TH, Gane E, Moyes C, et al. Serological and clinical outcomes of horizontally transmitted chronic hepatitis B infection in New Zealand Maori: results from a 28-year follow-up study. Gut, 2015, 64(6): 966-972.
29. Tseng TC, Liu CJ, Chen CL, et al. Higher lifetime chance of spontaneous surface antigen loss in hepatitis B carriers with genotype C infection. Aliment Pharmacol Ther, 2015, 41(10): 949-960.
30. Kim JH, Lee JH, Park SJ, et al. Factors associated with natural seroclearance of hepatitis B surface antigen and prognosis after seroclearance: a prospective follow-up study. Hepatogastroenterology, 2008, 55(82-83): 578-581.
31. Yip TC, Chan HL, Wong VW, et al. Impact of age and gender on risk of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J Hepatol, 2017, 67(5): 902-908.
32. Liu J, Yang HI, Lee MH, et al. Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma. Gut, 2014, 63(10): 1648-1657.
33. Park YM, Lee SG. Clinical features of HBsAg seroclearance in hepatitis B virus carriers in South Korea: a retrospective longitudinal study. World J Gastroenterol, 2016, 22(44): 9836-9843.
34. Orito E, Hasebe C, Kurosaki M, et al. Risk of hepatocellular carcinoma in cirrhotic hepatitis B virus patients during nucleoside/nucleotide analog therapy. Hepatol Res, 2015, 45(8): 872-879.
35. Fwu CW, Chien YC, Kirk GD, et al. Hepatitis B virus infection and hepatocellular carcinoma among parous Taiwanese women: nationwide cohort study. J Natl Cancer Inst, 2009, 101(14): 1019-1027.
36. Qu LS, Liu JX, Zhang HF, et al. Effect of serum hepatitis B surface antigen levels on predicting the clinical outcomes of chronic hepatitis B infection: A meta-analysis. Hepatol Res, 2015, 45(9): 1004-1013.
37. Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int, 2016, 10(1): 1-98.
38. Lok AS, Mcmahon BJ. Chronic hepatitis B: update 2009. Hepatology, 2009, 50(3): 661-662.
39. Yuen MF, Wong DK, Sablon E, et al. HBsAg seroclearance in chronic hepatitis B in the Chinese: virological, histological, and clinical aspects. Hepatology, 2004, 39(6): 1694-1701.
40. Seto WK, Tanaka Y, Wong DK, et al. Longitudinal profiles of highly sensitive hepatitis B surface antigen levels: re-evaluation of HBsAg seroclearance. Liver Int, 2016, 36(5): 642-650.

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