Article

As the years of antiviral treatment for chronic hepatitis B increase, we are witnessing persistence of the risk for hepatocellular carcinoma (HCC). Even with successful control of hepatitis B virus (HBV) replication over a decade (even over 12 years), there remains the risk for HCC in patients with chronic hepatitis B (CHB).

Currently, HCC is the second most common cancer death.¹ Worldwide, the majority of HCC is causatively associated with chronic HBV infection.^2–5 In 2006, with their landmark 12-year prospective study, Chen and his colleagues discovered that the high baseline HBV DNA level was closely associated with the high risk for the development of HCC.⁶

Treatment with nucleos(t)ide analogues (NAs), which began with lamivudine in 1998, has resulted in significant improvement in the survival of patients with CHB with the reduced incidence of HCC. These findings were observed with lamivudine.^7,8, entecavir⁹ and tenofovir.¹⁰

Nonetheless, as the duration of antiviral treatment increases, there still remains the risk for HCC in spite of undetectable HBV DNA in serum for years as reported by different investigators^11–15 with the observation time of 4-5 years including ours.¹⁴ As shown in the table 1, our experience shows the longest years of successful viral suppression before the development of HCC. The maximum treatment period before HCC was 18.7 years. The longest time of negative serum HBV DNA was 12.4 years as shown in the table below.¹⁴

Table 1. Development of HCC in patients with cirrhosis on long-term antiviral therapy

Pt	Date start Tx	Change in Child Class On Tx	Date HCC Dx	Size (cm) and site of HCC	Sex & Age (yr) at HCC Dx	Yrs on anti-HBV Tx at HCC Dx	HBVDNA at HCC Dx	Yrs with undetectable HBV DNA Before HCC Dx	Anti-HBV Tx	Status
3	5/1998	A->A	2/2008	1.8x0.9 Lt	76 F	9.8	UD	6.7	LAM+TDF	alive
6	2/2004	A->A	6/2013	2.5 Lt	57 M	9.3	UD	7.7	TDF	dead
7	2/1996	A->A	7/2013	1.6x1.4 Rt	73 M	17.4	UD	9.7	TDF	alive
9	5/1996	A->A	10/2014	3.4 Rt	74 M	18.4	UD	10.4	LAM+TDF	alive
10	2/2000	A->A	4/2015	3.4x3.4 Rt	62 M	15.2	UD	12.4	TDF	alive

Note: UD: undetectable, LAM:lamivudine, TDF:tenofovir disoproxil fumarate
Average years on antiviral therapy: Average 14 years with a median of 15.2 years (9.3-18.4 yrs)
Average years with undetectable HBV DNA: median 9.7 years (6.7-12.4)
This table is from Ref. 14 (Minerva Gastroenterol Dietol 2017;63:74-76)

Persistent risk for HCC is attributed to the inability of eradicating the HBV with the current treatment using NAs. The NA’s are effective in suppressing the replication of HBV but do not eliminate the covalently closed circular DNA (cccDNA), the template for viral replication which is located inside the nucleus of the hepatocytes.

Hepatocarcinogenesis by HBV can be multifactorial and integration of HBV DNA into the host DNA is considered one of the most important mechanisms. This integration would lead to rearrangement of chromosomes, deregulation and instability of gene expression that leads to oncogenesis.^16–18

In order to cure the HBV infection, several approaches may be needed; eradication of the cccDNA, inhibition of viral entry from the serum to the newly formed hepatocytes, T cell vaccine which targets specifically HBV DNA, enhancing the host immune activity including the innate immunity with toll-like receptor agonists and suppression of viral replication. Additional approach would be an inhibition of maturation of the pregenomic mRNA in the hepatocyte nucleus and block its export to hepatocyte cytoplasm. The process would cut down the generation of HBV core particle in the cytoplasm which would significantly reduce the production of cccDNA.

While the cure for hepatitis C virus infection has become possible with the direct-acting antivirals recently developed, cure for HBV is still far from achievement. Fortunately, multiple compounds with potential HBV cure are being identified by the scientists in the world and the massive effort for HBV eradication is in progress.^19,20 We look forward to achieving our long-waited cure of HBV infection.

References

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136(5): E359–E386
2. Rani M, Yang B, Nesbit R. Hepatitis B control by 2012 in the WHO Western Pacific Region: rationale and implications. Bull WHO. 2009; 87: 707–713.
3. Sanyal AJ, Yoon SK, Lencioni R. The etiology of hepatocellular carcinoma and consequences for treatment. Oncologist. 2010; 15(Suppl 4): 14–22.
4. Szabó E, Páska C, Kaposi PN, et al. Similarities and differences in hepatitis B and C virus induced hepatocarcinogenesis. Pathol Oncol Res. 2004; 10(1): 5–11.
5. Gurtsevitch VE. Human oncogenic viruses: hepatitis B and hepatitis C viruses and their role in hepatocarcinogenesis. Biochemistry (Mosc). 2008; 73(5): 504–513.
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.
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: 1521–1531.
8. Eun JR, Lee HJ, Kim TN, et al. 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(1): 118–125.
9. 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(1): 98–107.
10. 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(20): 3631–3638.
11. Papatheodoridis GV, Manolakopoulos S, Touloumi G, et al. Virological suppression does not prevent the development of hepatocellular carcinoma in HBeAg-negative chronic hepatitis B patients with cirrhosis receiving oral antiviral(s) starting with lamivudine monotherapy: results of the nationwide HEPNET. Greece cohort study. Gut. 2011; 60(8): 1109–1116.
12. Papatheodoridis GV, Lampertico P, Manolakopoulos S, et al. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol. 2010; 53(2): 348–356.
13. Vlachogiannakos J, Papatheodoridis G. Hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy. World J Gastroenterol. 2013; 19(47): 8822–8830.
14. Dargan A, Wong SY, Coben R, et al. Persistent risk for hepatocellular carcinoma after more than a decade of successful hepatitis B virus suppression. Minerva Gastroenterol Dietol. 2017; 63(1): 74–76.
15. Ando Y, Ishigami M, Ishizu Y, et al. Cumulative incidence and risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B who achieved sustained disappearance of viremia by nucleos(t)ide analogue treatment. Hepatol Res. 2017 (in press).
16. Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterol. 2004; 127(5 Suppl 1): S56–S61.
17. Fourel G, Trepo C, Bougueleret L, et al. Frequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumours. Nature. 1990; 347(6290): 294–298.
18. Matsubara K, Tokino T. Integration of hepatitis B virus DNA and its implications for hepatocarcinogenesis. Mol Biol Med. 1990; 7(3): 243–260
19. Wang X-Y, Chen H-S. Emerging antivirals for the treatment of hepatitis B. World J Gastroenterol. 2014; 20(24): 7707–7717.
20. Zeisel MB, Lucifora J, Mason WS, et al. Towards an HBV cure: state-of-the-art and unresolved questions--report of the ANRS workshop on HBV cure. Gut. 2015; 64(8): 1314–1326.