Postoperative Antiviral Therapy With Nucleos(t)ide Analogs in Patients With Hepatitis B Virus--Related Hepatocellular Carcinoma

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To the Editor:
We were excited to read the impressive article just published in Annals of Surgery showing that postoperative nucleos(t)ide analog (NA) therapy significantly reduced late hepatocellular carcinoma (HCC) recurrence and improved overall survival in patients with hepatitis B virus (HBV)--related HCC after curative resection.1 Given that the 5-year recurrence rate remains around 75% in patients with intermediate and advanced-stage HCC,2 the article by Huang et al comes at an important time, and we would like to propose several important issues raised in this study.
Indirect antitumor effects of NAs include the following points. First, prolonged suppression of HBV replication with NAs may reduce the risk of HBV-related HCC development. Second, patients with higher serum hepatitis B viral load have a significantly higher risk of HCC development and HCC recurrence after resection. Reduction in hepatitis B viral load can reduce the rate of HCC development and recurrence. Third, through inhibiting hepatitis activity and reducing chronic inflammation in the remnant liver, NAs may improve hepatic functional reserve after resection and then increase the chances for further treatment.
In this study, 100 patients with HBV-related HCC and high serum hepatitis B viral load (>2000 IU/mL) received postoperative adefovir (10 mg/d) therapy orally starting from 4 to 7 days after surgery. The important issue is the fact of HBV reactivation caused by resection, which significantly correlated to the prognosis of the patients after resection. Even in the patients with low serum hepatitis B viral load (<2000 IU/mL) before surgery, 19.1% patients have HBV reactivation after resection.3 Antiviral therapy significantly reduces the rate of HBV reactivation.4 Therefore, initiation of antiviral therapy in those with detectable serum HBV DNA before resection may be the best option. On the other hand, chronic hepatitis B cirrhosis strongly predicts HCC development and disease-related mortality. Moreover, NAs therapy is well tolerated and has benefits in maintaining preserved liver function. So, patients with HBV-related HCC and undetectable HBV DNA before surgery may also receive postoperative NAs therapy after resection. Treatment duration was not reported by this study. Because NAs therapy cannot completely eradicate HBV and the need to reduce HBV replication as much as possible, treatment duration until HBsAg seroconversion may be not enough.
All the included patients with Child-Pugh A liver function in this study underwent R0 resection. The first question is whether patients with Child-Pugh B or C liver function will tolerate postoperative NAs therapy. NAs therapy can rapidly suppress the level of HBV DNA and improve the liver function in chronic hepatitis B patients with decompensated cirrhosis5 or in patients with HBV-related HCC.4 Postoperative NAs therapy may render patients with HBV-related HCC better able to tolerate HCC treatments and improve their prognosis. The second question is about tumor stage. Patients with advanced-stage HCC have high early tumor recurrence rate and low long-term overall survival rate. The effect of postoperative NAs therapy may be overshadowed by aggressive tumor characteristics of advanced-stage HCC. So, the efficacy of postoperative NAs therapy would be more pronounced in patients with early-stage HCC.6
In this study and the first randomized controlled trial,7 adefovir and lamivudine were used, respectively. The major problem with long-term monotherapy of NAs is drug resistance. Lamivudine (22%)7 and adefovir (15%)1 have the highest rate of drug resistance, whereas entecavir (1.2%)8 and tenofovir (0%)9 have the lowest drug resistance and minimal toxicity. Moreover, with the potent antiviral efficacy, entecavir and tenofovir can achieve long-term effective HBV DNA suppression. Therefore, the application of more potent antiviral agents with entecavir or tenofovir on the perioperative HCC patients may have a greater survival benefit.

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