Hepatocellular Carcinoma Risk With Tenofovir vs Entecavir for Chronic Hepatitis B

Secondary liver cancer. Light micrograph of a section through liver tissue showing a secondary cancer that had metastasised (spread) from a primary small cell lung cancer. Magnification: x250 when printed at 10 centimetres wide.
Researchers question study results that show tenofovir disoproxil fumarate is associated with a significantly lower risk for hepatocellular carcinoma compared with entecavir in treatment-naïve patients with chronic hepatitis B.

In a letter to editors1, published in Gastroenterology, the authors raise several issues for consideration when interpreting results from a study2 conducted in China that concluded that tenofovir disoproxil fumarate (TDF) may be associated with a significantly lower risk of developing hepatocellular carcinoma (HCC) compared with entecavir in treatment-naïve patients with chronic hepatitis B (CHB). The letter authors noted that the claims are inconsistent with previous literature, including some of their own results2, which found, “no long-term differences, including the risk of developing HCC, between treatment-naïve patients with CHB treated with [entecavir] vs. TDF.”

The concerns addressed in the letter included the existence of substantial differences in baseline characteristics of the patients treated with entecavir and vs those who received TDF, as well as a significantly biased patient distribution of 95% vs 5% of the study cohort to each treatment group, respectively. There is also the possibility of selection bias as a result of the retrospective nature of the study using data from the Clinical Data Analysis and Reporting System with, “considerable missing data including [hepatitis B virus e antigen] status (19.7%), HBV DNA level (35.7%), and serum creatinine (10.6%).” According to letter authors these limitations could not be completely corrected via the statistical adjustments used by investigators.

Specifically, it was pointed out that the percentage of patients with liver cirrhosis was too low among the TDF group (2.9% vs 13.6% of patients treated with entecavir). Patients treated with entecavir were also significantly older, even after propensity score matching (absolute standardized difference, 0.11). Therefore, the risk for HCC in this group may have been overestimated because of the higher frequency of cirrhosis and older age. They added, “older patients tend to have more comorbidities such as metabolic syndrome, which is associated with an increased risk of HCC development.” Body mass index was also not reported and, “due to the possible adverse effects of TDF, physicians might have been more likely to prescribe [entecavir] rather than TDF for older patients or those with diabetes and decreased renal function.” Taken together, the letter authors believe these issues strongly suggest that the superiority in terms of long-term prognosis of both drugs requires further confirmation in prospective studies.

The letter authors also raised concerns about the later introduction of TDF into Hong Kong compared with other countries, despite the use of 1:5 propensity matching to overcome the difference. It is possible that between the introduction of entecavir and TDF the criteria for antiviral therapy was eased, allowing for the initiation of antiviral therapy at a less severe stage of CHB. It is therefore a possibility that TDF was used more recently in patients with less severe disease, which could afford advantages to TDF and improve prognosis. The letter authors suggested a subgroup analysis of selected patients who were treated with entecavir or TDF only after the introduction of TDF. They also believe more detailed information on the time sequence of TDF introduction, changes in antiviral therapy criteria, and the prescription percentage of entecavir and TDF at each time interval, is required.

Concerns regarding antiviral agent switching were also raised, because the letter authors noted that this process was not well described in the article. They recommended that the numbers of patients switching and the reasons for the switch be described. High rates of switching from entecavir, for example, might mean unidentified exposure to lamivudine or other low-genetic barrier drugs, while switching from TDF might indicate TDF was not tolerable or induced potential adverse events.

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The letter authors acknowledged that, “this topic would be an important issue for some time,” but believe randomized controlled trials might not be feasible in the near future. In conclusion they recommend that current international guidelines for the management of CHB patients should not be influenced by current studies because solid answers have not yet been provided on the topic.


  1. Lee HA, Seo YS, Kim SU. Risk of hepatocellular carcinoma with Tenofovir vs. Entecavir in patients with chronic hepatitis B. [published online March 19 2020]. Gastroenterology. doi:10.1053/j.gastro.2019.11.314.
  2. Yip TC, Wong VW, Chan HL, Tse YK, Lui GC, Wong GL. Tenofovir is associated with lower risk of hepatocellular carcinoma than Entecavir in patients with chronic HBV infection in China. Gastroenterology. 2020;158: 215-225.e6.