Antiviral Therapy and Hepatitis B Virus–Related Hepatocellular Carcinoma Recurrence

Abstract

To the Editor: Although using antiviral therapy to suppress hepatitis B virus (HBV) replication after curative resection of hepatocellular carcinoma (HCC) is thought to potentially reduce the rate of HCC recurrence, studies regarding the efficacy of nucleoside analogues in this clinical setting are limited and thus controversial. In the study by Dr Wu and colleagues, the authors used the Taiwan National Health Insurance Research Database for analysis and reported that the use of a nucleoside analogue was associated with a lower risk of HCC recurrence among patients with HBV-related HCC after liver resection. Their results support the use of antiviral therapy in the tertiary prevention of HCC. However, several issues need be clarified before extrapolating their results to other eligible patients with HBV-related HCC after curative treatment. First, curative surgical resection is usually defined by an adequate free resection margin on the resected hepatic specimen, plus no clinical or radiological evidence of tumor recurrence within 12 months after resection. However, the pathological details of surgical specimens are not included in the Taiwan database. Therefore, possible misclassification of patients with HCC as curative resection in this study may confound early or late HCC recurrence after surgery, as mentioned in the Editorial by Lok. Second, reimbursement for nucleoside analogue use in Taiwan is granted only to patients in high-risk populations and requires patients to be followed up for at least 6 months before enrollment or to have hepatic decompensation. Therefore, baseline liver disease status, remnant liver function, adherence to follow-up, and health care received may have been different between treated and untreated patients. Although the authors used complex statistical methods to adjust for possible confounding factors, these inherent differences cannot be adjusted for in their analyses. Third, according to the regulations of the Taiwan program, all treated patients need to refill anti-HBV agents monthly, suggesting the follow-up interval between the 2 groups after surgical resection may also be different. The trends in cumulative incidence rates of HCC recurrence and overall mortality were different between treated and untreated patients, even in the first year. This finding contradicts previous studies that found high viral loads and hepatic inflammatory activities to be associated with late HCC recurrence. Because the time from viral infection to tumor development is long, the markedly reduced rates of HCC recurrence and overall mortality within 1 year of curative resection are not anticipated, and there may be other possible mechanisms to explain these unusual observations.