Journal List > Korean J Gastroenterol > v.74(5) > 1138090

Lee: Long Term Efficacy of Antiviral Therapy: Mortality and Incidence of Hepatocellular Carcinoma

Abstract

Multiple studies have shown that oral antiviral therapies reduced the incidence of hepatocellular carcinoma (HCC) and improved the survival of patients with chronic hepatitis B when compared with that of untreated patients. In particular, entecavir and tenofovir share the qualities of high efficacy in reducing the HBV DNA levels, and they have excellent tolerability and safety. These drugs modified the natural history of liver fibrosis, improve liver function, decrease the incidence of HCC, decrease the need for liver transplantation, and improve survival. Many studies have suggested that long-term antiviral therapy reduces the risk of HCC and liver cirrhosis in patients with chronic hepatitis. The mechanism of these drugs in reducing the risk of HCC is not clear. This article reviews the mechanisms of carcinogenic HBV by conducting a review of the literature on the efficacy of therapy for reducing the risk of HCC. A few recent articles have suggested that tenofovir offers advantages over entecavir in terms of HCC prevention, but these articles have the inherent limitations of observational data. No other head-to-head randomized trials exist. Further randomized studies would help provide stronger evidence of the association between the type of antiviral agent and the HCC outcomes. Only achieving complete viral eradication from the liver will truly decrease the mortality and incidence of HCC.

Notes

Financial support None.

Conflict of interest None.

References

1. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015; 386:1546–1555.
2. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol. 2019; 25:93–159.
3. Ministry of Health and Welfare. Korea health statistics 2017: Korea national health and nutrition examination survey (KNHANES VII-2). Cheongju: Ministry of Health and Welfare;2017.
4. Kim BH, Park JW. Epidemiology of liver cancer in South Korea. Clin Mol Hepatol. 2018; 24:1–9.
5. Bae SH, Yoon SK, Jang JW, et al. Hepatitis B virus genotype C prevails among chronic carriers of the virus in Korea. J Korean Med Sci. 2005; 20:816–820.
6. Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology. 2002; 122:1756–1762.
7. Grandjacques C, Pradat P, Stuyver L, et al. Rapid detection of genotypes and mutations in the pre-core promoter and the pre-core region of hepatitis B virus genome: correlation with viral persistence and disease severity. J Hepatol. 2000; 33:430–439.
8. Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology. 2008; 135:459–467.
9. Lee KJ, Han KH, Chun JY, et al. Natural history of chronic hepatitis type B throughout long-term follow-up. Korean J Gastroenterol. 1997; 29:343–351.
10. Liu S, Zhang H, Gu C, et al. Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst. 2009; 101:1066–1082.
11. Tseng TC, Liu CJ, Yang HC, et al. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. Gut. 2015; 64:292–302.
12. Jang JW, Chun JY, Park YM, et al. Mutational complex genotype of the hepatitis B virus X /precore regions as a novel predictive marker for hepatocellular carcinoma. Cancer Sci. 2012; 103:296–304.
13. Kim JK, Chang HY, Lee JM, et al. Specific mutations in the enhancer II/core promoter/precore regions of hepatitis B virus subgenotype C2 in Korean patients with hepatocellular carcinoma. J Med Virol. 2009; 81:1002–1008.
14. Kao JH, Chen PJ, Lai MY, Chen DS. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers. Gastroenterology. 2003; 124:327–334.
15. Bravi F, Tavani A, Bosetti C, Boffetta P, La Vecchia C. Coffee and the risk of hepatocellular carcinoma and chronic liver disease: a systematic review and meta-analysis of prospective studies. Eur J Cancer Prev. 2017; 26:368–377.
16. Zhou YY, Zhu GQ, Liu T, et al. Systematic review with network meta-analysis: antidiabetic medication and risk of hepatocellular carcinoma. Sci Rep. 2016; 6:33743.
17. Lee M, Chung GE, Lee JH, et al. Antiplatelet therapy and the risk of hepatocellular carcinoma in chronic hepatitis B patients on antiviral treatment. Hepatology. 2017; 66:1556–1569.
18. Kim G, Jang SY, Nam CM, Kang ES. Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study. J Hepatol. 2018; 68:476–484.
19. Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010; 51:422–430.
20. Liaw YF, Raptopoulou-Gigi M, Cheinquer H, et al. Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study. Hepatology. 2011; 54:91–100.
21. Wong GL, Chan HL, Mak CW, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology. 2013; 58:1537–1547.
22. Lim YS, Han S, Heo NY, Shim JH, Lee HC, Suh DJ. Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine. Gastroenterology. 2014; 147:152–161.
23. Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013; 58:98–107.
24. Ahn J, Lim JK, Lee HM, et al. Lower observed hepatocellular carcinoma incidence in chronic hepatitis B patients treated with entecavir: results of the ENUMERATE study. Am J Gastroenterol. 2016; 111:1297–1304.
25. Cho H, Ahn H, Lee DH, et al. Entecavir and tenofovir reduce hepatitis B virus-related hepatocellular carcinoma recurrence more effectively than other antivirals. J Viral Hepat. 2018; 25:707–717.
26. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008; 359:2442–2455.
27. Marcellin P, Gane E, Flisiak R, et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance: 8 year results from two phase 3 trials. Hepatology. 2014; 60:313A–314A.
28. Kim WR, Loomba R, Berg T, et al. Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B. Cancer. 2015; 121:3631–3638.
29. 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; 381:468–475.
30. Chan HL, Sung JJ. Hepatocellular carcinoma and hepatitis B virus. Semin Liver Dis. 2006; 26:153–161.
31. Liu CJ, Chen BF, Chen PJ, et al. Role of hepatitis B virus precore/ core promoter mutations and serum viral load on noncirrhotic hepatocellular carcinoma: a case-control study. J Infect Dis. 2006; 194:594–599.
32. Chemin I, Zoulim F. Hepatitis B virus induced hepatocellular carcinoma. Cancer Lett. 2009; 286:52–59.
33. Bonilla Guerrero R, Roberts LR. The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma. J Hepatol. 2005; 42:760–777.
34. Feitelson MA, Lee J. Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Lett. 2007; 252:157–170.
35. Murakami Y, Saigo K, Takashima H, et al. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut. 2005; 54:1162–1168.
36. Kew MC. Hepatitis B virus x protein in the pathogenesis of hepatitis B virus-induced hepatocellular carcinoma. J Gastroenterol Hepatol. 2011; 26 Suppl 1:144–152.
37. Hsieh YH, Su IJ, Wang HC, et al. Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis. 2004; 25:2023–2032.
38. Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol. 2005; 5:375–386.
39. Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA function in hepatitis B virus infection. J Hepatol. 2009; 51:581–592.
40. Neuveut C, Wei Y, Buendia MA. Mechanisms of HBV-related hepatocarcinogenesis. J Hepatol. 2010; 52:594–604.
41. 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; 295:65–73.
42. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004; 351:1521–1531.
43. Eun JR, Lee HJ, Kim TN, Lee KS. Risk assessment for the development of hepatocellular carcinoma: according to on-treatment viral response during long-term lamivudine therapy in hepatitis B virus-related liver disease. J Hepatol. 2010; 53:118–125.
44. Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther. 2008; 28:1067–1077.
45. Choi J, Kim HJ, Lee J, Cho S, Ko MJ, Lim YS. Risk of hepatocellular carcinoma in patients treated with entecavir vs tenofovir for chronic hepatitis B: a Korean nationwide cohort study. JAMA Oncol. 2019; 5:30–36.
46. Kim SU, Seo YS, Lee HA, et al. A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in South Korea. J Hepatol. 2019; 71:456–464.
47. Yip T Cheuk-Fung, Wong V Wai-Sun, Chan H Lik-Yuen, Tse YK, Lui G Chung-Yan, Wong G Lai-Hung. Tenofovir is associated with lower risk of hepatocellular carcinoma than entecavir in patients with chronic HBV infection in China. Gastroenterology. 2019; 09. 28. [Epub ahead of print].
48. Kim GA, Lim YS, Han S, et al. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B. Gut. 2018; 67:945–952.
49. Sinn DH, Lee J, Goo J, et al. Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load. Hepatology. 2015; 62:694–701.
50. Kuang XJ, Jia RR, Huo RR, et al. Systematic review of risk factors of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J Viral Hepat. 2018; 25:1026–1037.
TOOLS
ORCID iDs

Hyun Woong Lee
https://orcid.org/0000-0002-6958-3035

Similar articles