Nucleos(t)ide analogs reduce the risk of hepatitis B‐associated hepatocellular carcinoma: A can't miss proposition?
Authors: Neil Mehta, Francis Y. Yao
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. See Article on Page 1517 Hepatocellular carcinoma (HCC) is one of the most common causes of death worldwide and is often related to underlying chronic hepatitis B infection (CHB). When HCC is diagnosed at an early stage, there are three potentially curative treatment options. Liver transplant results in excellent recurrence‐free survival, but organ shortage often limits the availability of this option. Surgical resection is the preferred treatment for HCC in the absence of cirrhosis or in well‐compensated cirrhosis without portal hypertension. The third option, radiofrequency ablation (RFA), has traditionally been reserved for nonsurgical candidates, but is gaining acceptance as an alternative first‐line treatment to resection for a small solitary tumor given that RFA has a lower morbidity and similar long‐term outcomes when compared to resection.1 In both resection and RFA, the cumulative risk of HCC recurrence or development of new HCC exceeds 50% at 5 years.1 No neoadjuvant therapy, including sorafenib,2 has so far been shown to reduce HCC recurrence or improve survival after resection or ablation. Another approach to reducing HCC recurrence after curative resection or RFA is to target the underlying viral hepatitis. It has been shown that active inflammation and subsequent damage and regeneration of hepatocytes are associated with an increased risk of HCC in chronic viral hepatitis and in postoperative remnant livers. Furthermore, a study on gene‐expression signature has suggested that the extent of liver damage and the presence of protein‐inflammatory milieu may result in an increased risk of postsurgical HCC recurrence.3 However, the largest randomized, control trial using interferon (IFN)‐alpha after resection in predominantly CHB patients has shown no significant effect on HCC recurrence.4 The lack of a clear benefit of IFN in reducing postsurgical HCC recurrence may be a result of the low rate of sustained virological suppression resulting from this treatment. Nucleos(t)ide analogs (NAs) are highly effective in suppressing viral replication in CHB and have been suggested, in one study, to reduce HCC recurrence and improve survival after resection.5 In this issue of Hepatology, Lee et al. are the first to explore the impact of NA initiation post‐RFA on HCC recurrence.6 In this large retrospective cohort study of newly diagnosed CHB‐associated solitary HCC using the Taiwanese National Health Insurance Research Database, the outcomes of 133 patients who received NAs for at least 90 days post‐RFA were compared to 266 patients never treated with NAs and matched for age, sex, presence of cirrhosis, tumor size, and date of RFA. Only patients without evidence of HCC recurrence for at least 3 months post‐RFA were included. The majority had a tumor <3 cm (74%) and cirrhosis (73%). The investigators found a significant reduction in the cumulative incidence of HCC recurrence within 2 years of RFA in the NA group (42%) versus the untreated group (54%). However, the difference in the HCC recurrence rates between the two groups was no longer significant at 3 years (53% vs. 58%), possibly because of the short duration of NA treatment (median of 1.5 years). In multivariable analysis, patients who received NA treatment had a 31% decreased risk of HCC recurrence compared to those without treatment. The only stronger predictor was the presence of cirrhosis. In subgroup analysis, NA treatment appeared to have a protective effect against recurrence regardless of age, tumor size, and presence of cirrhosis. Figure 1 summarizes the effects of NA on HCC recurrence and survival post‐RFA in the present study6 and after resection in a previous publication using the same database.5 Though NA reduces HCC recurrence in both the resection and RFA groups, NA confers a survival benefit only in the postresection group. The short length of NA treatment post‐RFA and that 70% of patients had less than 2 years of follow‐up might have limited the ability to detect a survival benefit of NA treatment post‐RFA. Not surprisingly, patients treated with RFA were older and had more advanced liver disease compared to patients treated with resection and might be at greater risk of death from causes other than HCC recurrence.Figure 1: Cumulative incidence of HCC recurrence and overall mortality with and without NAs at 2 years after RFA6 and resection.5There are several limitations of the study by Lee et al. Owing to the short length of NA treatment after RFA as well as the short duration of follow‐up, the full effects of NA cannot be ascertained. Ideally, the findings of this study should be confirmed by prospective, randomized, controlled trials. Conducting such a trial is difficult at present when a strong argument can be made that all patients with cirrhosis with CHB regardless of viral load should receive NA therapy. Nearly three quarters of the patients in this study had cirrhosis, and the latest American Association for the Study of Liver Disease guidelines7 recommend NA treatment even if the hepatitis B DNA level is less than 2,000 IU/mL regardless of alanine transaminase (ALT) to reduce the risk for hepatic decompensation. Another drawback of this study is the lack of information on baseline viral load and ALT to determine whether the effects of NA depend on these factors, and which subgroups according to viral load and ALT would derive the greatest benefit from NA therapy. These limitations notwithstanding, this study provides further evidence supporting the association between NA therapy and HCC risk reduction in CHB. In a randomized, controlled study from Asia,8 lamivudine in patients with CHB and compensated cirrhosis was associated with a significantly lower risk of disease progression (9% vs. 21%) and a reduced risk for HCC development (3.9% vs. 7.4%) at 3 years compared to placebo. In a study from Korea,9 patients with compensated CHB cirrhosis, hepatitis B DNA <2,000 IU/mL, and normal ALT had a nearly 10% incidence of HCC within 5 years and NA therapy was associated with a significantly decreased HCC risk. Most recently, a multicenter study demonstrated a 77% risk reduction in HCC incidence with NA treatment compared to those without, after adjusting for age, sex, ALT, and hepatitis B DNA.10 Importantly, the reduction in HCC risk was independent of the presence of cirrhosis. In summary, the study by Lee et al.6 is the first to support a role of NA therapy in reducing the risk of HCC recurrence post‐RFA. This study also adds to the growing body of literature suggesting substantial benefits of NA therapy in CHB, specifically in reducing hepatic decompensation in patients with cirrhosis, decreasing the incidence of HCC, and improving outcomes for those with HCC after resection or ablation. For more and more patients with CHB, particularly those with cirrhosis, NAs appear to be a "can't miss" proposition.