Letter: which patients with hepatitis B virus-related hepatocellular carcinoma should receive nucleos(t)ide analogue therapy?

Abstract

We read with great interest the recent study by Wong et al.1 examining the efficacy of oral nucleos(t)ide analogue therapy in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Those authors concluded that nucleos(t)ide analogue treatment reduced risk of HCC recurrence and mortality in patients who had previously been treated with surgical resection, local ablative therapy, transarterial chemoembolisation (TACE) or combinations of these treatments. The work by Wong et al.1 significantly extends previous studies of nucleos(t)ide analogue therapy in patients with HBV-related HCC,2, 3 in part because their cohort is such a large, ethnically homogeneous group covering 70–80% of the Hong Kong population. At the same time, their work leaves an important question unanswered: is nucleos(t)ide analogue therapy safe and effective for all subpopulations of patients? Patients with HBV-related HCC can vary widely in preoperative serum levels of HBV DNA and tumour stage, yet these factors were not considered in the analysis by Wong et al.1 Official guidelines recommend nucleos(t)ide analogue therapy only for patients with serum HBV DNA levels >2000 IU/mL. In addition, those authors' own subgroup analyses indicate that nucleos(t)ide analogue treatment benefited those patients who had received resection, but not those who had received TACE or the combination of resection and TACE. This may reflect the fact that only 10% of the study population had received palliative treatments such as TACE. In addition, the efficacy analysis did not include patients who had received supportive care. Since more than 90% of the study population had received resection or local ablative therapies, we interpret the results of Wong et al.1 as demonstrating good efficacy in patients with early- or intermediate-stage HBV-related HCC, but they do not allow conclusions about the benefit of NA therapy for patients with advanced disease. Several studies in the literature already suggest that post-operative nucleos(t)ide analogue therapy can significantly reduce tumour recurrence and mortality among patients with HBV-related HCC after TACE.4-6 This is consistent with the idea that post-operative nucleos(t)ide analogue therapy improves patient outcomes in the short term by reducing the risk of HBV reactivation and improving liver function,4, 5 while in the long term, it suppresses viral replication and reduces chronic inflammation in the remnant liver, thereby reducing the risk of de novo HCC recurrence. It is possible that with longer follow-up, the patients in the Wong et al.1 cohort who received TACE would have shown clinical benefit; unfortunately, those authors did not report median follow-up. It is also possible that patients in the Wong et al.1 cohort who received TACE had high pre-TACE serum levels of HBV DNA, which have been associated with poor overall survival and rapid HCC progression after TACE.7 In fact, TACE by itself can reactivate HBV replication and increase risk of HCC recurrence.4 We caution against using the results of Wong et al.1 to guide decisions about nucleos(t)ide analogue therapy in patients with advanced HBV-related HCC. Instead, we highlight substantial evidence from several previous studies supporting nucleos(t)ide analogue therapy in patients with HBV-related HCC and serum HBV DNA levels >2000 IU/mL who have previously received palliative treatments such as TACE.8 For patients with early- or intermediate-stage HCC, the efficacy of nucleos(t)ide analogue therapy has been amply demonstrated in previous work2, 3, 9, 10 as well as in the study by Wong et al.1 Declaration of personal interests: None. Declaration of funding interests: This research was funded by the National Natural Science Foundation of China (81560460/H1602, 81260088/H0322).