Nucleos(t)ide analogue therapy for HBV-related HCC after hepatic resection: clinical benefits and unanswered questions

Abstract

Hepatic resection (HR) and radiofrequency ablation (RFA) remain the most frequent curative therapies for hepatocellular carcinoma (HCC) because of strict indications for liver transplantation and shortages of donated livers. Nevertheless, recurrence occurs in up to 75 % of patients with intermediate or advanced HCC at 5 years after HR [1]; in these patients, 5year recurrence-free survival (RFS) is lower than 25 %, and tumor recurrence is the main cause of death [2]. Therefore, inhibiting tumor recurrence is a key to improving HCC patients’ overall survival (OS). Hepatitis B virus (HBV) is the most common cause of HCC around the world, which inspired clinicians to treat patientswith HBV-relatedHCC usingnucleos(t)ideanalogues (NAs) to inhibit HBV replication and therefore reduce risk of HCCincidence.HighHBVloadandreplicationareassociated with greater risk of HCC incidence [3], and large studies with long follow-up have shown that NA therapy can dramatically reduce HCC incidence and death in patients with liver cirrhosis who are chronically infected with HBV [4, 5]. NA therapy also appears to reduce risk of HCC recurrence after HR [6, 7], suggesting that it may improve OS for patients with HBVrelated HCC after curative HR or RFA. Many retrospective studies have suggested that adjuvant NA therapy does reduce risk of HBV-related HCC recurrence after curative treatments [7–19]. Meta-analysis of these studies have concluded that NA therapy is associated with significantly lower tumor recurrence and liver-related mortality and significantly higher OS in patients with HBV-related HCC than no adjuvant therapy after curative treatments [20, 21]. Unfortunately, the retrospective design of these studies limits the strength of their evidence. The strongest evidence of whether NA therapy offers clinical benefits would come, in principle,fromarandomizedcontrolledtrial(RCT).However, carrying out an RCT is ethically and logistically difficult because oral NA therapy has already proven effective at preventingdisease progression inpatientschronically infected with HBV and because such therapy is becoming more affordableand doesnot cause significant sideeffects. Therefore, few patients with HBV-related HCC would volunteer for an RCT.