Journal of Hepatology
Volume 41, Issue 3 , Pages 482-484, September 2004

Out of control: hepatitis B reactivation by transarterial treatment of hepatocellular carcinoma

Department of Medicine II, University of Freiburg, Hugstetter Strasse 55, D-79106 Freiburg, Germany

published online 19 August 2004.

See Article, pages 427–435

Article Outline

 

Hepatitis B virus (HBV) infection is one of the most common viral diseases affecting man. According to WHO an estimated 2 billion people—one third of the world's population—has been exposed to HBV [1] and more than 400,000 individuals are chronically infected at present [2], despite the availability of a safe and efficient vaccine. The risk of chronicity depends among others on the age at infection: perinatal transmission results in more than 90% chronic infections as compared to less than 5% when infection is acquired in adulthood. Mostly due to perinatal transmission, chronic HBV infection is highly endemic in Asia and subSaharan Africa with HBsAg prevalence rates of up to 10–20%, while much lower numbers (0.2–0.5%) are observed in Europe and North America, where sexual transmission and intravenous drug use are the major routes of infection [2].

Chronic HBV carriers have a 100-fold increased risk of developing hepatocellular carcinoma (HCC) and this risk increases with the duration of infection, significant liver damage, male gender and other factors [3], [4]. The annual incidence of HBV-induced HCC is about 300,000. Thus, HBV infection accounts for about 60% of all HCC cases worldwide [2]. Notably, HCC has also been detected in cases of occult (HBsAg negative, HBV DNA positive) HBV infection, which may further increase this number [5], [6]. The prognosis of untreated HCC is poor and current treatment options are limited. Some patients with early stage HCC will be eligible for surgical resection, liver transplantation or percutaneous ablations strategies. Metaanalysis has revealed that transarterial chemoembolization is the only treatment improving survival in carefully selected patients with unresectable HCC [3].

Given these figures, it comes as no surprise that many HBV-infected, mostly Asian patients presenting with unresectable HCC are currently being evaluated for transarterial treatment. Systemic chemotherapy can induce HBV reactivation and this can represent a serious clinical problem, most notably in the setting of bone marrow transplantation [7], [8], [9], [10], [11], [12], [13], [14]. It is assumed that through therapy-induced immunosuppression HBV replication goes unchecked and the virus can spread throughout the liver. Recovery of immune function then triggers cytopathic virus elimination resulting in massive liver damage. This raises the question whether local chemotherapy might have the same effect. Case reports have demonstrated that this might be indeed the case [14], [15]. However, data from large studies have not been available thus far.

In this issue of the Journal, Jang et al. report a retrospective analysis of HBV replication and HBV-induced liver damage in HCC patients treated with transarterial chemo-lipiodolization (TACL) [16]. Patients were assigned to this treatment regimen according to standard criteria developed by the Barcelona Clinic Liver Cancer (BCLC) Group [17]. All patients were HBsAg positive and the majority of patients had a preserved liver function (Child-Pugh A). In 75.9% of patients epirubicin combined with cisplatin was administered along with lipiodol. No embolization was performed. HBV reactivation was defined as reappearance or 10-fold increase of HBV DNA and liver damage was defined as a more than threefold ALT increase exceeding 100IU/l (reference range <36IU/l). Lamivudine treatment was started in patients with HBV reactivation when ALT levels increased to >2× the upper limit of normal. Among 83 patients undergoing TACL, 28 (33.7%) had HBV reactivation and 18 (21.7%) developed hepatitis attributed to HBV, 3 of whom died despite lamivudine therapy. By contrast, HBV reactivation was observed in only 2/63 (3.2%) patients receiving other treatments, one of whom developed clinical hepatitis. The authors concluded that TACL represents an important risk factor for HBV reactivation.

Despite of some limitations, this study provides important information and raises interesting questions. First, who carries the greatest risk for reactivation? Based on the current pathogenetic model outlined above one would assume that high viral load predicts a worse outcome. Since HBeAg positivity correlates with high replication levels, one would expect that HBeAg positive patients have a higher risk of HBV reactivation and overt hepatitis than HBeAg negative patients. Surprisingly, while HBeAg was predictive of virological HBV reactivation, neither HBeAg nor HBV DNA were predictors of overt hepatitis B. One of the reasons accounting for this observation might be the relatively high cut-off level in the branched DNA assay (0.7×106copies/ml). Indeed, in the study some patients were HBeAg positive but HBV DNA negative. For more accurate assessment of the HBeAg status and the respective HBV DNA levels it would have been useful to present data on the presence of anti-HBe antibodies and to quantify HBV DNA by real time PCR. Nevertheless, high baseline HBV replication levels are not a prerequisite for clinical hepatitis B reactivation, as evidenced in patients receiving systemic chemotherapy [7], [8], [9], [10], [11], [12], [13], [14]. Next, HBV genotypes might influence the clinical outcome. Initial studies have suggested that genotype C is associated with a worse clinical outcome compared with genotype B [18]. With respect to HCC treatment, patients infected with genotype B seem to have better response rates to embolization therapy and lower HCC recurrence as compared to patients infected with genotype C [19]. Definitive conclusions, however, have to await critical appraisal of ongoing studies. Finally, though not an issue in Southeast Asia, co-infection with delta virus might represent a risk factor.

Interestingly, ALT-levels were also not predictive of reactivation of hepatitis; histological data on necroinflammatory activity were not presented. If neither HBV markers nor baseline ALT levels predicted the reactivation of hepatitis, how can we be sure that the hepatitis was not due to factors other than HBV reactivation? The strongest point supporting a pathogenetic role of HBV was the time interval between the last course of TACL and hepatic decompensation. Seven patients with clinical reactivation of hepatitis B experienced hepatic decompensation with a median interval of 33 days (range: 24–43). By comparison, in the absence of HBV reactivation the median interval was 3 days (range: 2–6), suggesting a direct cytotoxic effect of transarterial treatment.

Collectively, the evidence seems compelling that TACL may indeed cause a clinically important HBV reactivation. The factor(s) contributing to HBV reactivation and hepatitis remain to be further defined. The TACL protocol applied in this study utilized lipiodol mixed with standard chemotherapeutic agents without subsequent embolization, that is an integral part of most transarterial treatment protocols. Nevertheless, HBV reactivation can occur in both settings [15]. All transarterial treatment protocols cause extensive cell damage. One immediate consequence is stimulation of liver regeneration, which may directly influence HBV replication. However, studies in a HBV transgenic mouse model suggest that HBV replication is rapidly downregulated by cytokines in regenerating livers following partial hepatectomy [20]. On the other hand, treatment-induced cell damage should also affect non-hepatocytes, most notably immune cells. This raises the interesting possibility that local cytotoxicity generates a temporary knock-down of local immune control, providing a window of opportunity for enhanced HBV replication.

Irrespective of the precise pathogenetic mechanism(s) this study raises an important practical issue: when and whom should we treat with nucleos(t)ide analogues? This and other studies have shown that lamivudine can be effective. However, timing is important and death related to HBV reactivation despite lamivudine therapy is not infrequent [15], [16]. Preemptive treatment has been successfully performed in patients treated for lymphoma and in bone marrow recipients [11]. Further, with the availability of adefovir and more nucleos(t)ide analogues in the pipeline, the selection of resistant mutants is no longer a pressing issue in this context. It seems justified, therefore, to preemptively treat all HBsAg positive patients scheduled for transarterial therapy of HCC. Ideally, clinical studies should be performed in order to define the optimal timing and duration of the antiviral treatment. On a broader perspective and beyond preemptive treatment related to TACL, major efforts should be focused on the worldwide implementation of vaccination programs and the early treatment of HBV-related liver disease to effectively prevent the development of HCC, for which therapeutic options are still very limited.

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References 

  1. WHO. World Health Report 1996: fighting disease, fostering development. Geneva: World Health Organization; 1996;
  2. Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet. 2003;362:2089–2094
  3. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907–1917
  4. Bruix J, Boix L, Sala M, Llovet JM. Focus on hepatocellular carcinoma. Cancer Cell. 2004;5:215–219
  5. Yano Y, Yamashita F, Sumie S, Ando E, Fukumori K, Kiyama M, et al. Clinical features of hepatocellular carcinoma seronegative for both HBsAg and anti-HCV antibody but positive for anti-HBc antibody in Japan. Am J Gastroenterol. 2002;97:156–161
  6. Pollicino T, Squadrito G, Cerenzia G, Cacciola I, Raffa G, Crax A, et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology. 2004;126:102–110
  7. Clark FL, Drummond MW, Chambers S, Chapman BA, Patton WN. Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high grade non Hodgkin's lymphoma see comments. Ann Oncol. 1998;9:385–387
  8. ter Borg F, Smorenburg S, de Man RA, Rietbroek RC, Chamuleau RA, Jones EA. Recovery from life threatening, corticosteroid unresponsive, chemotherapy related reactivation of hepatitis B associated with lamivudine therapy. Dig Dis Sci. 1998;43:2267–2270
  9. Ahmed A, Keeffe EB. Lamivudine therapy for chemotherapy induced reactivation of hepatitis B virus infection. Am J Gastroenterol. 1999;94:249–251
  10. Al-Taie OH, Mork H, Gassel AM, Wilhelm M, Weissbrich B, Scheurlen M. Prevention of hepatitis B flare up during chemotherapy using lamivudine: case report and review of the literature. Ann Hematol. 1999;78:247–249
  11. Yeo W, Steinberg JL, Tam JS, Chan PK, Leung NW, Lam KC, et al. Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy in process citation. J Med Virol. 1999;59:263–269
  12. Hoofnagle JH, Dusheiko GM, Schafer DF, Jones EA, Micetich KC, Young RC, et al. Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med. 1982;96:447–449
  13. Yeo W, Chan PK, Zhong S, Ho WM, Steinberg JL, Tam JS, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol. 2000;62:299–307
  14. Tamori A, Nishiguchi S, Tanaka M, Kurooka H, Fujimoto S, Nakamura K, et al. Lamivudine therapy for hepatitis B virus reactivation in a patient receiving intra-arterial chemotherapy for advanced hepatocellular carcinoma. Hepatol Res. 2003;26:77–80
  15. 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;138:691–692
  16. Jang WJ, Choi JY, Bae SH, Kim CW, Yoon SK, Cho SH, et al. Transarterial chemo-lipiodolization can reactivate hepatitis B virus replication in patients with hepatocellular carcinoma. J Hepatol. 2004;41:427–435
  17. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology. 2002;35:519–524
  18. Kao JH, Chen DS. Global control of hepatitis B virus infection. Lancet Infect Dis. 2002;2:395–403
  19. Tsubota A, Arase Y, Ren F, Tanaka H, Ikeda K, Kumada H. Genotype may correlate with liver carcinogenesis and tumor characteristics in cirrhotic patients infected with hepatitis B virus subtype adw. J Med Virol. 2001;65:257–265
  20. Guidotti LG, Matzke B, Chisari FV. Hepatitis B virus replication is cell cycle independent during liver regeneration in transgenic mice. J Virol. 1997;71:4804–4808

PII: S0168-8278(04)00314-9

doi:10.1016/j.jhep.2004.07.005

Journal of Hepatology
Volume 41, Issue 3 , Pages 482-484, September 2004

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