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Recently, comparative effectiveness research (CER) has received attention as an underestimated yet valuable research methodology in the field of liver diseases. CER is particularly useful for research questions for which prospective randomized trials are not feasible due to time, cost or ethical issues. Furthermore, cost-effectiveness or economic aspect of health problems may also be included in CER. The downsides of CER, however, sometimes weaken the level of evidence from those studies; for example, unidentified biases and confounders. Although using electronic medical records of a large patient population has facilitated CER, biases and confounders may significantly limit the credibility of such studies, especially retrospective ones. The methodological countermeasures to overcome these shortcomings include setting an appropriate comparison group to investigate the effectiveness of a new intervention and securing adequate statistical power. Management of patients with chronic hepatitis B (CHB) has shown remarkable advances in the last decade, most importantly by virtue of the development and clinical use of antiviral agents. For example, risk of decompensation and development of hepatocellular carcinoma (HCC) was reduced with prolonged virological response under long-term antiviral therapy. In this issue of Gut and Liver, Kim et al. covers an intriguing topic on the choice of antiviral agent for patients with hepatitis B virus (HBV)-related HCC in their large-scale cohort study. In this retrospective CER, the authors concluded that entecavir (ETV) was superior to lamivudine (LAM) in newly diagnosed HBVrelated HCC patients who did not receive antiviral therapy prior to diagnosis, in terms of overall survival, decompensation-free survival, and recurrence-free survival. Wong et al. reported that ETV-treated patients with cirrhosis achieved reduction in the risk of hepatic events, HCC development, liver-related and allcause mortality. A retrospective study from Korea also reported lower risk of death or transplantation with ETV compared with LAM. Apart from the role of antiviral therapy in prevention of liver-related events in patients with CHB only (i.e., prior to the development of HCC), the endpoints of Kim et al.’s study included survival, decompensation and recurrence in patients with HBV-related HCC; Were all these endpoints appropriate to be analyzed? To answer this question, it needs to be reminded that the study subjects had two distinct yet interacting diseases, i.e., chronic liver disease (mostly cirrhosis) plus malignancy (HCC). A recent study by Wong et al. investigated the effect of antiviral treatment with nucleos(t)ide analogues (NAs) on the outcome of HCC patients after different treatments. In this large-scale retrospective study (n=2,198), beneficial effect of NA treatment was most prominent in patients who underwent surgical resection by reducing recurrence risk (adjusted hazard ratio [HR], 0.58) while the risk reduction was not significant in subgroups with local ablation, transarterial chemoembolization or combination treatments. Regarding the survival benefit, tendency towards better survival was observed in NAtreated patients compared with NA-untreated patients, without statistical significance. Although this study from Hong Kong did not primarily intend to compare the relative effectiveness between different NAs, results of subgroup analysis comparing LAM versus ETV were also included, showing that reduction in postoperative recurrence was greater with ETV than LAM (HR, 0.64; p=0.008); however, no difference was observed in survival benefit between patients treated with either one of these two

Comparative Effectiveness of Lamivudine versus Entecavir in Patients with Hepatocellular Carcinoma: Watch out for Confounders!