Author Affiliations: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China (Wei Q, Xu X, Ling Q, Zhou B and Zheng SS)

Corresponding Author: Shu-Sen Zheng, MD, PhD, FACS, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China (Tel/Fax: 86-571-87236567; Email: zyzss@zju.edu.cn)

 

© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(13)60041-7

Contributors: WQ and XX proposed the study and wrote the first draft. All authors contributed to the design and interpretation of the study and to further drafts. ZSS is the guarantors.

Funding: This work was supported by grants from the National High Technology Research and Development Program of China (863 Program 2012AA020204), the Program of Zhejiang Medical and Health Platform (2011ZDA007) and Program for New Century Excellent Talents in University (NCET).

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: After effective treatment with antiviral agent, patients with low serum hepatitis B virus (HBV) DNA level had a low incidence of hepatocellular carcinoma (HCC). HBV reactivation after HCC surgery is associated with HCC recurrence. To date, there are no universal guidelines for the perioperative antiviral treatment of patients with chronic hepatitis B, let alone antiviral therapy in patients with HBV-related HCC. The present analysis is trying to develop a perioperative anti-HBV treatment protocol.

 

DATA SOURCES: A literature search of PubMed was performed, the key words were "perioperative" "antiviral therapy", "hepato-cellular carcinoma" and "chronic hepatitis B". All of the information was collected.

 

RESULTS: Relevant documents showed that reactivation of HBV replication played a direct role in the late recurrence of HCC after surgical resection. The well control of viral load before and after operation significantly increased tumor-free survival. Many drugs are used in antiviral therapy including interferon alpha and nucleoside analogues. Foscarnet, two-agent or even multiagent of nucleoside analogues is necessary for perioperative antiviral treatment of patients with chronic hepatitis B related HCC.

CONCLUSIONS: HBV reactivation after HCC surgery induces hepatitis flare and hepatocarcinogenesis, thus lifelong and vigorous control of HBV is very important in patients with chronic hepatitis B and HBV-related HCC. A uniform guideline is necessary to rapidly reduce HBV DNA to a lower level in perioperation.

 

 

KEY WORDS: hepatitis B virus; hepatocellular carcinoma; antiviral therapy

 

 

Hepatocellular carcinoma (HCC), a highly prevalent and lethal cancer, is the third leading cause of cancer-related death worldwide.^[1] HBV infection is a risk factor for HCC and HBV-related HCC is a leading cause of cancer death in China.^[2] As a curative treatment, partial hepatectomy provides potentially curative outcome for HCC patients who are indicated for this procedure.^[3-5] However, the tumor recurrence rate after surgery remains high, with a 5-year recurrence rate of more than 70% in most studies.^[6-9] Recently, accumulating evidence has shown that for patients with HBV infection, a high serum HBV DNA level either before or after operation is associated with higher risk of HCC recurrence.^[10-17] In addition, hepatectomy could reactivate HBV replication, especially in patients who did not receive any antiviral therapy.^[11] Reactivation of HBV replication occurred in 28% patients after liver resection for HCC.^[18] A previous study^[19] showed that antiviral therapy after hepatectomy conferred a survival benefit in patients with HBV-related HCC. Thus, to prevent postoperative HCC recurrence, effective antiviral therapy should be initiated in patients with a high preoperative serum HBV DNA level.

 

A recent meta-analysis found that antiviral therapy with nucleotide analogues decreased HCC-related mortality and HCC recurrence after surgery, and improved overall survival in patients with hepatitis B related HCC.^[20] However, for patients undergoing surgical treatment for HBV-related HCC, most of the studies focused on the antiviral therapy after resection, whereas studies focused on the antiviral therapy before resection are rare. Preoperative antiviral therapy is recommended for HBV carriers who are going to receive partial hepatectomy. In addition, there is no universally accepted protocol to eradicate/decrease viral load perioperatively for patients with HBV-related HCC undergoing partial hepatectomy.

 

 

Perioperative high HBV DNA level is related to posto-perative HCC recurrence, thus, effective suppression of serum HBV DNA level is a marker of efficacy for antiviral therapy.^[21] Because operative treatment should be performed soon after the diagnosis of resectable HCC. Perioperative anti-HBV therapy not only rapidly reduces HBV DNA level in a short period of time, but also effectively prevents HBV DNA rebound after operation. The following is some therapeutic schemes used currently.

 

The first agent for a successful treatment of chronic hepatitis B (CHB) was IFN-α. IFN-α has both antiviral and antiproliferative properties. Some meta-analyses have shown that IFN-α has a beneficial effect on HBeAg eradication and sustained reduction in serum HBV DNA level.^{[22, 23]}

 

Although one review of more than one thousand CHB patients found that IFN-α had no or minimal overall effect in preventing HCC, some interferon-responders indeed had a beneficial outcome.^[24] This study indicated that it is the direct anti-HBV effect of IFN-α that plays an important role in preventing HCC recurrence, not its immune modulation and antitumorgenesis. In addition, a recent published meta-analysis of 1180 HBV/HCV patients, enrolled in nine randomized trials and four cohort studies, showed that conventional IFN-α improved the 1-, 2-, and 3-year recurrence-free survival by 7.8%, 35.4% and 14.0%, respectively.^[25] These studies provided promising effects of IFN-α in preventing HCC recurrence and prolonging survival, while the effect of interferon therapy in preventing HBV-related HCC recurrence was controversial.^{[26, 27]} To investigate the effect of adjuvant IFNα-2b on the recurrence-free survival of patients with postoperative viral hepatitis-related HCC, Chen et al^[28] conducted a randomized, observation-controlled and phase III trial showing that adjuvant IFNα-2b only temporarily suppressed viral replication during the period of treatment but it was not effective in reducing the postoperative recurrence of HCC.

 

Besides, the sustained antiviral response is only 30%-40%. IFN-α is associated with numerous adverse effects, some of which can be severe.^[23] In patients with advanced liver disease, IFN-α therapy may have a significant risk of hepatic decompensation with life-threatening complications including icterus, hepatic encephalopathy, ascites, variceal bleeding or death.^[29]

 

Long-term follow-up showed that a majority of patients still have detectable HBV DNA after interferon treatment.^{[30, 31]} In addition, most studies^{[32, 33]} failed to demonstrate a reduced incidence of HCC.

 

Currently five NAs are approved in the treatment of CHB. They are lamivudine, adefovir dipivoxil (ADV), telbivudine, entecavir and tenofovir disoproxil fumarate (TDF). These agents can be used against HBV, HCV, herpes simplex, and HIV. During the last decade, the rise of oral NAs has changed the treatment landscape for HBV infections. It is confirmed that NAs slow the progression from severe liver disease to cirrhosis as well as to HCC.^[34]

 

The first agent of NAs is lamivudine which is an oral NA that inhibits DNA synthesis by terminating the nascent proviral DNA chain. It rapidly reduces both serum HBV DNA level and transaminase concentra-tions.^[35] Lamivudine is the primary antiviral agent in the majority of patients, and it is well known that lamivudine not only delays the disease progression but also reduces the incidence of HCC. A research showed that HCC occurred in 3.9% of the patients treated with lamivudine; the incidence rate of HCC was 7.4% in the placebo group.^[36] These results indicated that anti-HBV nucleoside therapy may be a useful approach to reduce the recurrence of HCC in patients with HBV-related HCC after surgery. A recent study^[37] on patients treated with lamivudine (100 mg/d) showed that lamivudine may be effective in improving disease-free survival after resection of HBV-related HCC in patients with a high viral load. Chan and colleagues^[19] recommended that lamivudine was the first choice in antiviral therapy after hepatectomy. However, Chan and coworkersalso demonstrated the high potency of entecavir against HBV DNA activity. A more recent study on patients with advanced HBV-related HCC revealed that single use of lamivudine could neither reduce the short-term recurrence of HCC nor improve the disease-free survival.^[38]

 

TDF was initially approved for the treatment of HIV infection and then for treatment of CHB in 2008. Given the potent antiviral efficacy, low resistance rate and minimal toxicity, TDF can achieve a long-term effective HBV DNA suppression and has the potential to become one of the "ideal" treatment options for CHB.^[39] However, there were no validated data so far for the application of TDF on the perioperative antiviral treatment.

 

The major problem with long-term monotherapy of NAs is drug resistance. The incidence rate of lamivudine resistance was about 14%-39%.^{[37, 38, 40]} The cumulative rate of genotypic resistance to ADV in 5 years was 20%-29%.^{[41, 42]} The rate of resistance to telbivudine was 25.1% in HBeAg-positive patients and 10.8% in HBeAg-negative patients in 2 years.^[43] A study^[44] showed a very low rate (1.2%) of viral resistance to entecavir in a long-term treatment of CHB.

 

From the studies above we summarized that a monotherapy of NAs should be avoided in most cases. If initial monotherapy fails, a second drug with a nonoverlapping resistance profile should be added.^[45] In a study,^[38] lamivudine was used at an oral dose of 100 mg per day, starting within the first postoperative week. When YMDD mutation was confirmed, ADV tablets at a dose of 10 mg per day was added. As a result, the overall survival was improved for those patients with postoperative antiviral therapy.

 

Due to drug resistance, application of two-agent or even multiagent of NAs is necessary. In many centers, lamivudine-based antiviral therapy was recently applied to patients after hepatic resection for HBV-related HCC and it was found to improve liver function, decrease the risk of liver failure and HCC recurrence.^{[17, 37, 46]} The addition of adefovir to ongoing lamivudine therapy could achieve the excellent virological and biochemical response in lamivudine-resistant patients. However, these combinations had no effect on the suppression of hepatocarcinogenesis.^[47] Jayakumar et al^[48] found that entecavir plus tenofovir was more effective in reducing the HBV DNA level than lamivudine plus adefovir. However, combined lamivudine and adefovir was not too inferior, especially when cost of treatment was taken into consideration.

 

Foscarnet (PFA), a viral DNA polymerase inhibitor, is initially used in the treatment of herpes viral infection. It is a structural mimic of the anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases at concentrations that do not affect human DNA polymerases.^[49] PFA is administered by intravenous infusion with the advantage that it can be applied to fasting patients who can not use the antiviral drugs administered orally. In addition, the effect of intravenous infusion is more reliable than that of oral administration. So PFA fits the requirement of rapidly reducing HBV DNA level in a short term. PFA has been used in the patients with hepatitis B. Han and colleagues^[50] found that PFA inhibited HBV DNA replication in HBV-transfected human HepG2 cells and reduced serum HBeAg and HBV DNA copies in patients. However, a large, random and controlled clinical trial is needed to evaluate the antiviral effect of PFA.

 

A phase II clinical trial has been performed in the First Affiliated Hospital, Zhejiang University School of Medicine (Title: Perioperative hepatitis B virus load control strategies and molecular mechanisms of anti-recurrence and metastasis in hepatic cancer. Registration number: ChiCTR-TRC-11001683). The adult patients with untreated HCC, HBsAg positive and HBV DNA ≥10⁴/mL were enrolled in this trial. According to the perioperative antiviral therapy, the patients were randomly divided into lamivudine, lamivudine+PFA, lamivudine+ADV and entecavir groups. The perioperative anti-HBV effect will be observed and compared. This is the first research in the world that focused on finding appropriate perioperative antiviral treatment of HBV-related HCC. This trial will be helpful in establishing a protocol to reduce postoperative HBV and HCC recurrence.

 

 

The optimal antiviral treatment duration for HBV-related HCC is still unknown. HBeAg seroconversion is a milestone in the treatment of CHB and an index for withdrawing antiviral treatment. Current Asian-Pacific guidelines suggest that treatment with NAs can be discontinued when HBeAg seroconversion with undetectable HBV DNA on 2 separate occasions at least 6 months apart in HBeAg-positive patients.^[51] Furthermore, although the serum viral load was well controlled, the high level of HBV cccDNA has been found in some cases. cccDNA is an indicator of HBV replication in tumor tissues.^[52] HBV is known to play the central role in liver carcinogenesis mainly via integration of the HBV genome into the host chromosome and expression of trans-activating factors. Since HCC is the final outcome of HBV-induced inflammatory damage and gene mutations, lower thresholds of viraemia to initiate therapy and long-term antiviral therapy should be performed in the patients with HBV-related HCC compared with those without HCC. After HCC surgery, lifelong antiviral treatment is essential to control the viral load and to suppress the hepatocarcinogenesis, regardless of HBeAg seroconversion.

 

 

The well control of viral load before and after operation improves tumor-free survival. Most of the studies are related to antiviral therapy after resection, but very few focus on the antiviral therapy for HCC before resection. In addition, although current analysis suggests that HBV reactivation after HCC surgery induce hepatitis flare and hepatocarcinogenesis, there are no universally accepted guidelines of perioperative antiviral therapy for the patients with HBV-related HCC. A prospective, randomized and controlled clinical trial is necessary to establish a treatment guideline for these patients.

 

 

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