Reply to Letter: “Adjuvant Antiviral Therapy With Nucleos(t)ide Analogs in Patients With Hepatitis B Virus--Related Hepatocellular Carcinoma”

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Reply:
We thank Zhong and colleagues for their interest in our paper.1
As clearly stated, adjuvant adefovir was started 4 to 7 days after surgery in our study.1 As only patients with hepatocellular carcinoma (HCC) were included in this study, our patients were only randomized after histopathologic confirmation of HCC to exclude patients with intrahepatic cholangiocarcinoma, which happened in about 10% of our patients with primary intrahepatic cancer undergoing liver resection.
When our study began in 2007, the American Association for the Study of Liver Diseases2 issued a guideline recommending that patients with HBV-DNA of more than 2000 IU/mL (104 copy/mL) receive antiviral treatment, while those with HBV-DNA below 2000 IU/mL were not recommended to receive such a treatment. However, we believed that hepatitis B–related HCC patients with low HBV-DNA should still receive antiviral treatment because liver resection depresses a patient's immunity and viral reactivation can happen at the postoperative period, thus compromising the results of survival. Our later studies showed that viral reactivation happened in 19% of patients even with low HBV-DNA3 and these patients also had other beneficial effects of antiviral therapy.3,4 As underlying liver function is an important prognostic factor for long-term survival of patients after liver resection, we only included patients with Child's A liver function in our study to ensure consistency in the baseline preoperative liver function in the 2 groups. It was also our belief that patients with Child's B or C should be given antiviral treatment before liver surgery as this treatment significantly improves the patient's liver function and can even reserve fibrosis/cirrhosis of the underlying liver.5
Many studies have shown that postoperative antiviral treatment, if started preoperatively or in the early postoperative periods, improves long-term results of HCC patients after liver resection.3,6,7 The beneficial effects include improving the underlying liver function, preventing antiviral reactivation, relieving chronic hepatic inflammation, reversing liver fibrosis, reducing incidence of HCC recurrence, and eventually improving patients’ overall survival.3,5–7 Thus, antiviral treatment should be given to all hepatitis B-related HCC patients undergoing liver resection, transarterial chemoembolization, radiofrequency ablation or systemic chemotherapy.8–10
Lamivudine, adefovir, and entecavir were recommended as the first line of antiviral therapy in the 2007 guidelines. Tenofovir was not listed then. Adefovir was chosen in this study as entecavir was not easily available to us at that time. It was not until 2009 that entecavir and tenofovir were recommended as the first-line antiviral therapy in the North American Guidelines.11
We agree that antiviral drugs with low resistance and high potency should be chosen as the first-line antiviral treatment. Currently, entecavir is the recommended first-line necleot(s)ide to be used and tenofovir is still not listed. The treatment should be started early, preferably before liver resection and the treatment should be for a long time, if not life-long.

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