SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. References

See article in J. Gastroenterol. Hepatol. 2012; 27: 158–164.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide especially in the Asia-Pacific region due to the endemic status of life-long chronic hepatitis B virus (HBV) infection.1 Curative treatments of HCC include surgical resection, local ablative therapies such as radiofrequency ablation, as well as liver transplantation. However, due to various patient and tumor factors, many patients suffering from HCC are not amendable to these curative treatments. Therefore, a significant proportion of HCC patients are subjected to transarterial chemo-embolization (TACE), which has been proven to improve patient survival.2

Patients with HBV-related HCC suffer not only from malignancy but also chronic HBV infection. It follows that treatments for HCC could also affect the activity of virus replication, a factor that has important implications for hepatitis activity. Most of the evidence concerning this aspect has come from studies of HCC patients who have received TACE, as TACE involves the administration of chemotherapeutic agents. Because these are usually mixed with lipiodol as a vehicle for their emulsification and tumor cell uptake and administered via hepatic arterial embolization, this raises concerns about HBV reactivation, a factor that itself might jeopardize a favorable patient outcome. However previous studies concerning the risks of HBV reactivation after TACE somehow showed inconsistent results. An early case report described three patients who developed HBV reactivation after TACE.3 A prospective cohort study from a Korean group then showed that TACE was an independent risk factor of HBV reactivation in HCC patients.4 In contrast, another Korean prospective study showed that the risk of HBV activation after TACE was low and similar to the control group who did not receive TACE.5 To further confuse matters, a cohort study from a Chinese group showed that TACE could even decrease serum HBV DNA levels.6

Data concerning the risk of HBV reactivation after hepatic resections have been lacking. In light of the curative intent of liver surgery, the clinical course of HBV infection for patients subjected to hepatic tumor resection may be even more clinically relevant than those receiving TACE. HBV reactivation in patients who have recently undergone hepatic resections can potentially lead to fulminant hepatitis, liver failure or even mortality, thereby significantly altering the hoped-for clinical outcome. As patients undergoing hepatic resections do not receive chemotherapy or immunosuppressive measures other than the surgery, they might not, theoretically, be expected to have a much increased risk of HBV reactivation. However, major surgery such as hepatic resections may significantly modulate or dampen immune responsiveness thereby possibly leading to significant immunosuppression.7

One small study of 55 HBV-related HCC patients found that 13 patients (24%) developed postoperative hepatitis; reactivation of viral replication was documented after hepatic resections in seven of the 25 patients in whom appropriate testing had been performed.8 However, the HBV reactivation observed in this study seems more likely to have been part of the natural history of HBV infection than a consequence of hepatic resections because features of the immune clearance phase (high preoperative alanine aminotransferase [ALT] and HBV DNA levels) were more evident among patients who developed postoperative HBV reactivation.8 Hence the exact role of hepatic resections on HBV activity remains unclear.

In this issue of the Journal of Gastroenterology and Hepatology, Huang and colleagues describe the results of their investigation on the perioperative HBV reactivation in patients undergoing surgery for HCC.9 This is a prospective cohort study with a respectable sample size, and the results fill the gaps of current evidence about HBV reactivation in the era of antiviral therapy. The authors found that 10 (6.1%) patients (of whom eight did not receive antiviral therapy prior to operation) among 164 developed HBV reactivation within one month of hepatic resections. Further, and not surprisingly, HBV reactivation was more common among those who were not receiving antiviral therapy (21%) compared with those who were (1.6%). One interesting point of this study is that a low preoperative HBV DNA (< 200 IU/mL [< 1000 copies/mL]) correlated with HBV reactivation on univariate analysis, but this correlation was no longer evident after adjusting for the lack of antiviral therapy, the only independent risk factor identified on multivariate analysis. Thus, the apparent correlation between low pre-operative HBV DNA level and HBV reactivation was likely secondary to the confounding effect of the use of antiviral therapy, which was not given in a randomized fashion but mainly to those with serum HBV DNA above 2000 IU/mL together with high ALT levels, according to international guidelines.

This study was also limited by lack of a control arm composed of HBV-related HCC patients not undergoing hepatic resections, so it remains unproven from this study as to whether liver surgery really increased the risk of HBV reactivation.

Despite of these limitations, this report by Huang and colleagues provides us with the important message clinically that HBV reactivation is possible after hepatic resections for HCC, even among patients who do not have the agreed indications for antiviral therapy, and the risk includes some individuals with low serum HBV DNA levels at the time of surgery. Perhaps it is pertinent to note that a single HBV DNA level at a given time is not always indicative of permanent immune-suppression of HBV replication, as indicated particularly by more recent analyses of the REVEAL data.10 The next question we need to ask is whether indiscriminate use of antiviral therapy to all HBV patients undergoing hepatic resections or segmental resections will further decrease the risk of HBV reactivation and hence improve the clinical outcomes. A recent meta-analysis provided indirect evidence of the possible beneficial roles of antiviral therapy by reducing HBV reactivation after the curative treatment of HCC.11 This meta-analysis found that antiviral therapy with nucleotide analogues has potential beneficial effects after the curative treatment of HBV-related HCC in terms of tumor recurrence, HCC-related mortality, liver-related mortality and overall survival. It particularly reduces death secondary to liver failure, which is possibly secondary to HBV reactivation, by an impressive 90%.11 In the studies included in this meta-analysis, patients who did or did not receive antiviral therapy had comparable serum HBV DNA as well as ALT levels (Table 1). As the mean serum HBV DNA level of these studies was around 5.5 logs IU/mL, it remains to be defined whether antiviral therapy should be given to patients with serum HBV DNA levels lower than those recommended by the international guidelines.

Table 1.  Mean hepatitis B virus DNA level and alanine aminotransferase (ALT) of the studies included in the meta-analysis.11
StudyMean HBV DNA Level (log copies/mL)Mean ALT (IU/L)
Antiviral therapyYesNoYesNo
  • Median values were presented.

  • ALT, alanine aminotransferase; N/A, not available.

Chuma et al. 200912N/AN/A4330
Hung et al. 200813N/AN/AN/AN/A
Koda et al. 2009145.75.27854
Kubo et al. 2007156.06.05356
Kuzuya et al. 2007166.24.15754
Li et al. 2010176.57.3N/AN/A
Piao et al. 2005186.16.58862
Shuqun et al. 200619N/AN/AN/AN/A
Yoshida et al. 200820N/AN/A5436
Total or median6.16.05655

References

  1. Top of page
  2. Abstract
  3. References
  • 1
    Chan HL, Sung JJ. Hepatocellular carcinoma and hepatitis B virus. Semin. Liver Dis. 2006; 26: 15361.
  • 2
    Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37: 42942.
  • 3
    Vizzini GB, Luca A, Marino IR. Hepatitis B virus reactivation after a single session of transarterial chemoembolization in patients with hepatocellular carcinoma. Ann. Intern. Med. 2003; 138: 6912.
  • 4
    Jang JW, Choi JY, Bae SH et al. Transarterial chemo-lipiodolization can reactivate hepatitis B virus replication in patients with hepatocellular carcinoma. J. Hepatol. 2004; 41: 42735.
  • 5
    Park JW, Park KW, Cho SH et al. Risk of hepatitis B exacerbation is low after transcatheter arterial chemoembolization therapy for patients with HBV-related hepatocellular carcinoma: report of a prospective study. Am. J. Gastroenterol. 2005; 100: 2194200.
    Direct Link:
  • 6
    Xu J, Wang YH, Xia JL et al. Effect of transcatheter arterial chemoembolization on HBV DNA level in primary liver cancer patients. Chin. J.Cancer 2009; 28: 15.
  • 7
    Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Miyazaki M. Immunosuppression following surgical and traumatic injury. Surg. Today 2010; 40: 793808.
  • 8
    Kubo S, Nishiguchi S, Hamba H et al. Reactivation of viral replication after liver resection in patients infected with hepatitis B virus. Ann. Surg. 2001; 233: 13945.
  • 9
    Huang L, Li J, Lau WY et al. Perioperative reactivation of hepatitis B virus replication in patients undergoing partial hepatectomy for hepatocellular carcinoma. J. Gastroenterol. Hepatol. 2012; 27: 15864.
  • 10
    Chen CJ, Yang HI. Natural history of chronic hepatitis B REVEALed. J. Gastroenterol. Hepatol. 2011; 26: 62838.
  • 11
    Wong JS, Wong GLH, Tsoi KK et al. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment. Pharmacol. Ther. 2011; 33: 110412.
  • 12
    Chuma M, Hige S, Kamiyama T et al. The influence of hepatitis B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma. J. Gastroenterol. 2009; 44: 9919.
  • 13
    Hung IF, Poon RT, Lai CL et al. Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection. Am. J. Gastroenterol. 2008; 103: 166373.
    Direct Link:
  • 14
    Koda M, Nagahara T, Matono T et al. Nucleotide analogs for patients with HBV-related hepatocellular carcinoma increase the survival rate through improved liver function. Intern. Med. 2009; 48: 1117.
  • 15
    Kubo S, Tanaka H, Takemura S et al. Effects of lamivudine on outcome after liver resection for hepatocellular carcinoma in patients with active replication of hepatitis B virus. Hepatol. Res. 2007; 37: 94100.
  • 16
    Kuzuya T, Katano Y, Kumada T et al. Efficacy of antiviral therapy with lamivudine after initial treatment for hepatitis B virus-related hepatocellular carcinoma. J. Gastroenterol. Hepatol. 2007; 22: 192935.
  • 17
    Li N, Lai EC, Shi J et al. A comparative study of antiviral therapy after resection of hepatocellular carcinoma in the immune-active phase of hepatitis B virus infection. Ann. Surg. Oncol. 2010; 17: 17985.
  • 18
    Piao CY, Fujioka S, Iwasaki Y et al. Lamivudine treatment in patients with HBV-related hepatocellular carcinoma—using an untreated, matched control cohort. Acta Med. Okayama 2005; 59: 21724.
  • 19
    Shuqun C, Mengchao W, Han C et al. Antiviral therapy using lamivudine and thymosin alpha1 for hepatocellular carcinoma coexisting with chronic hepatitis B infection. Hepatogastroenterology 2006; 53: 24952.
  • 20
    Yoshida H, Yoshida H, Goto E et al. Safety and efficacy of lamivudine after radiofrequency ablation in patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol. Int. 2008; 2: 8994.