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, 5-year 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 patients with HBV-related HCC using nucleos(t)ide analogues (NAs) to inhibit HBV replication and therefore reduce risk of HCC incidence. High HBV load and replication are associated 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][8][9][10][11][12][13][14][15][16][17][18][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, from a randomized controlled trial (RCT). However, carrying out an RCT is ethically and logistically difficult because oral NA therapy has already proven effective at preventing disease progression in patients chronically infected with HBV and because such therapy is becoming more affordable and does not cause significant side effects. Therefore, few patients with HBV-related HCC would volunteer for an RCT.Despite these obstacles, Yin et al. managed to publish in 2013 the first RCT examining the efficacy of adjuvant NA therapy in 180 patients newly diagnosed with HBV-related HCC after curative HR [22]. All patients had serum HBV DNA levels greater than 100 IU/mL. After median follow-up of 39.9 months, per-protocol analysis revealed that patients receiving lamivudine (100 mg/day) showed significantly higher short-and long-term RFS and OS than patients receiving no adjuvant therapy. In 2014, Huang and coworkers [23] performed an RCT examining the efficacy of adjuvant adefovir therapy in 200 patients newly diagnosed with HBVrelated HCC after curative HR. In contrast to the earlier RCT, all patients in this study had serum HBV DNA levels greater t...

Letter: should anti‐viral therapy be recommended for individuals chronically infected with hepatitis B virus and at low risk of hepatocellular carcinoma? Authors’ reply

“…CK-18, a marker of hepatocyte apoptosis, is useful to predict the presence of chronic liver injury, inflammatory activity in chronic hepatitis B virus infection, degree of liver fibrosis, presence of nonalcoholic steatohepatitis, and poor prognosis in liver cirrhosis. 7 Therefore, levels of CK-18 have been shown to be elevated in HCC, liver cirrhosis, hepatitis, nonalcoholic fatty liver disease and cholestatic liver disease. 7 Moreover, baseline serum levels of CK-18 are higher in HCC patients when compared to patients with liver cirrhosis.…”

“…7 Therefore, levels of CK-18 have been shown to be elevated in HCC, liver cirrhosis, hepatitis, nonalcoholic fatty liver disease and cholestatic liver disease. 7 Moreover, baseline serum levels of CK-18 are higher in HCC patients when compared to patients with liver cirrhosis. Bock et al compared CK-18 levels between patients who showed, or did not show, HCC regression after TACE.…”

Influence of antiviral therapy on survival of patients with hepatitis B-associated hepatocellular carcinoma undergoing transarterial chemoembolization

“…Other proposed mechanism states that reduction of hepatitis activity and chronic inflammation in remnant liver by the antiviral therapy improves hepatic functional reserve and helps patients to tolerate subsequent HCC treatment [21]. In present study, 54.…”

Feasibility of combining adjuvant transarterial chemoembolization with nucleos(t)ide analog therapy for patients with HBV-associated hepatocellular carcinoma after hepatectomy

“…Combination therapy may also be appropriate for patients with HBV-associated HCC in advanced stages. Although postoperative NA therapy in such patients may not significantly prolong their survival (22)(23)(24), it can decrease the rate of HBV reactivation and improve liver function (30,31). Two previous studies suggested that the combination of TACE and NA therapy in such patients can lead to significantly higher overall survival compared with TACE alone (32,33).…”