LAUSR

Hepatitis B virus (HBV) is an important risk factor for hepatocellular carcinoma (HCC) as it can lead to the development of HCC even in the absence of cirrhosis [1]. In the development of HCC, treatment for HBV will depend on the stage of the disease. Most patients will require antiviral therapy (AVT) as they have underlying cirrhosis. Management strategies for HCC are associated with the reactivation of HBV, which can lead to liver decompensation. Hence, the APASL guideline recommends starting AVT 1–2 weeks prior, during, and after locoregional therapies, resection, or LT in case of HBV-related HCC with detectable HBV DNA levels [2]. However, for HBV-related HCC patients with undetectable serum HBV DNA levels, limited data exist on the incidence and risk factors for HBV reactivation. In a recent issue of Digestive Diseases and Sciences, Chang et al. [3] retrospectively studied the long-term clinical outcomes of patients with HBV-related HCC with undetectable serum HBV DNA levels (< 12 IU/ml) at HCC diagnosis, comparing AVT-naïve patients with those on AVT. The authors reported that AVT-naïve status at HCC diagnosis was an independent predictor of HBV reactivation (detection of serum HBV DNA levels ≥ 12 IU/ml) and HBV flare (elevation of HBV DNA levels ≥ 2000 IU/ml) on follow-up. Surprisingly, HBV reactivation and HBV flare but not AVTnaïve status were independent predictors of overall survival. Although the study adds to the limited existing literature on this topic, a few issues need to be addressed. First, the study considered HBV mono-infected HCC patients by excluding patients with antibodies specific to hepatitis C virus (HCV) or human immunodeficiency virus (HIV). However, the prevalence of NAFLD is approximately 14–67% in Asian individuals with chronic HBV [4, 5], and in conjunction with NAFLD, HBV can exacerbate liver injury and increase the risk of developing cirrhosis, HCC, and mortality. Similarly, alcohol drinking, betel quid chewing, and cigarette smoking in patients with HBV infection are associated with an increased risk of HCC and mortality [6]. Hence, concomitant history of alcoholic liver disease (ALD) and NAFLD need to be considered and excluded before comparing the two groups. Second, the study does not provide information on the baseline liver function test, presence of cirrhosis, and ChildPugh score at the time of diagnosis of HCC. HBV genotype C, male sex, elevated aminotransferase levels, and ChildPugh score have been found to be independent predictors of HBV reactivation [7, 8]. Hence, the difference in both the groups with respect to the above factors could have led to a difference in the rate of reactivation and flare. Third, the definitions of HBV reactivation and flare mentioned in the study are arbitrary. In patients with previously undetectable HBV DNA levels, HBV reactivation is defined by APASL and AASLD guidelines as HBV DNA ≥ 2 log (100) IU/ml and ≥ 3 log (1000) IU/ml, respectively [1, 2]. AASLD defines HBV flare as an increase in ALT ≥ 3 times baseline and > 100 U/l [1], while APASL defines it as an elevation of aminotransferase to > 5 times the upper limit of normal and > 2 times the baseline value. The use of these definitions would have led to difference in the rate of reactivation and flare in both the groups. Even among patients with HCC who are HBsAg negative, occult HBV infection (OBI) has been associated with an increased risk of HCC. In a study of liver tissues from 90 HBsAg-negative patients with HCC, around 70% had OBI, among which 70% had HBV-DNA integration and 50% had cccDNA integration into the liver cells [9]. Transarterial chemoembolization (TACE) has also been found to be a risk factor for HBV reactivation in HBsAg-negative patients, * Suprabhat Giri [email protected]