Letters To The Editor Open Access
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. May 8, 2016; 8(13): 605-606
Published online May 8, 2016. doi: 10.4254/wjh.v8.i13.605
Antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after surgery: A comment for moving forward
Jian-Hong Zhong, Tian Yang, Bang-De Xiang, Le-Qun Li, Liang Ma
Jian-Hong Zhong, Bang-De Xiang, Le-Qun Li, Liang Ma, Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Tian Yang, Department of Hepatobiliary Surgery, Eastern Hepa-tobiliary Surgery Hospital, Second Military Medical University, Shanghai 201800, China
Author contributions: Zhong JH, Yang T and Xiang BD contributed equally to this work; Zhong JH designed the study and wrote the manuscript; Zhong JH, Yang T, Xiang BD, Li LQ and Ma L analyzed the data; all authors reviewed the manuscript.
Supported by The Guangxi University of Science and Tech-nology Research Projects, No. KY2015LX056; the Self-Raised Scientific Research Fund of the Ministry of Health of Guangxi Zhuang Autonomous Region, No. Z2015621, and No. Z2014241; the Innovation Project of Guangxi Graduate Education, No. YCBZ2015030; and the Guangxi Science and Technology Development Projects, No. 14124003-4.
Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Liang Ma, MD, Department of Hepato-biliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd #71, Nanning 530021, Guangxi Zhuang Autonomous Region, China. xitongpingjia@163.com
Telephone: +86-771-5330855 Fax: +86-771-5312000
Received: February 18, 2016
Peer-review started: February 19, 2016
First decision: March 1, 2016
Revised: March 4, 2016
Accepted: March 22, 2016
Article in press: March 23, 2016
Published online: May 8, 2016


Recurrence rate of hepatocellular carcinoma remains quite high even after surgery, and no postoperative therapies have been definitively shown to prevent hepatocellular carcinoma recurrence. A previous study showed that therapy with nucleos(t)ide analogues given to such patients after surgery significantly improved survival. However, many questions still exist about the usage of nucleos(t)ide analogues for patients with hepatocellular carcinoma after surgery.

Key Words: Antiviral therapy, Hepatocellular carcinoma, Hepatitis B virus, Unanswered question

Core tip: Some important points about the usage of nucleos(t)ide analogues for patients with hepatocellular carcinoma after surgery in clinic were pointed out.


Recurrence rate of hepatocellular carcinoma (HCC) remains quite high even after curative resection or radiofrequency ablation (RFA), and no adjuvant thera-pies have been definitively shown to prevent HCC recur-rence[1,2]. A previous study showed that therapy with nucleos(t)ide analogues (NAs) given to HCC patients after resection significantly improved survival[3]. Whether the same holds for HCC patients after RFA was unclear until Lee et al[4] reported their important findings that postoperative NA therapy significantly reduced 2-year recurrence rate. The authors supported their conclusions using multivariate analysis and propensity score match-ing. These results provide by far the strongest evidence that postoperative NA therapy can benefit patients with hepatitis B virus (HBV)-associated HCC. At the same time, methodological limitations in that study raise several important questions that must be addressed in future work.

Several of these limitations are acknowledged by Lee et al[4] in their report. They did not take into account possible confounding effects due to differences in base-line viral load, HBeAg, liver function, or type of treat-ment after recurrence. In addition, their focus on recurrence rate as the most important outcome and the relatively short (2-year) follow-up prevented them from clarifying how NA therapy provided clinical benefit. NA therapy is not thought to directly affect tumor growth. Rather, it is thought to act in the short term by reducing the risk of HBV reactivation and improving liver function. Lee et al[4] did not measure these outcomes in their study, making it impossible to examine how NA therapy reduced the recurrence rate. NA therapy is also thought to act in the long term by: (1) suppressing viral replication, which might reduce the risk of de novo HBV-related HCC development; and (2) reducing chronic inflammation in the remnant liver, thereby improving hepatic functional reserve after surgery and improving the patient’s treatment options. Lee et al[4] could not observe these mechanisms because they stopped follow-up at 2 years. As a result, Lee et al[4] were able to measure only early recurrence, not late recurrence, which occurs at least 2 years after surgery or RFA. The 2-year cut-off also prevented the authors from measuring overall survival, a key outcome for establi-shing the efficacy of any treatment.

The results of Lee et al[4] argue strongly for the therapeutic potential of postoperative NA therapy for patients with HBV-related HCC, but they fall short of definitively establishing the therapy as effective. To close this evidence gap, we recommend that future studies address the following questions[5]: (1) Do all patients with HBV-related HCC benefit from postoperative NA therapy? What are the indications for NA therapy? Should these indications include preoperative liver function and viral load? We note that most patients in the study by Lee et al[4] had early-stage tumors (< 3 cm) and cirrhosis. Also, all the patients in the former randomized controlled trial were all with relatively early-stage tumors[3]. In addition, almost all patients enrolled in previous studies had Child-Pugh A liver function[3,4,6,7]. So, further studies should investigate the benefit of NA therapy for patients with Child-Pugh B or C liver function. Last but not least, is NA therapy valuable for those with serum HBV DNA less than 500 copies/mL? (2) Which NA drug(s) are the most effective and safest? Lamivudine is the first antiviral drug. Although it suppresses the virus quickly, the frequency of drug resistance is too high. Other NA drugs include adefovir dipivoxil, entecavir, and tenofovir; (3) When is the optimal time to initiate NA therapy, and how long should it last? Nowadays, doctors and patients increasingly attach importance to the phenomenon of HBV reactivation. Therefore, NA therapy should be started before surgery. One of the purposes of NA therapy is to prevent tumor recurrence. Less than two years of therapy may be not enough; and (4) Are there benefits and risks to adding a second NA drug or continuing monotherapy? Many studies reported that combined therapy with two or more NA drugs were suitable for chronic hepatitis B. However, it is unknown for patients with HCC after surgery.

Addressing these questions will be essential for de-fining the NA treatment regimens most likely to provide clinical benefit, as well as for identifying the most suitable patient populations.


P- Reviewer: He JY, Qin JM, Ramos S S- Editor: Qiu S L- Editor: Wang TQ E- Editor: Liu SQ

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