Risk of hepatocellular carcinoma in antiviral treatment-naïve chronic hepatitis B patients treated with entecavir or tenofovir disoproxil fumarate: a network meta-analysis

Abstract

Background: Long-term antiviral treatments are associated with a significantly lower hepatocellular carcinoma (HCC) incidence in chronic hepatitis B (CHB) patients by reducing HBV DNA concentrations. However, it is still controversial whether antiviral strategies affect HCC development in antiviral treatment-naïve CHB patients. This study aimed to estimate the incidence of HCC in antiviral treatment-naïve CHB patients who were treated with Entecavir (ETV) and Tenofovir Disoproxil Fumarate (TDF) and compare the efficacy of two treatment regimens in HCC reduction.

Methods: The PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases were systematically searched until June 24, 2021. The pooled incidence and 95% confidence interval of HCC were calculated by the Freeman-Tukey double arcsine transformation method. The efficacies of ETV and TDF treatments in HCC reduction were compared through a network meta-analysis.

Results: A total of 27 studies were identified as eligible for this systematic review. The incidence densities in the ETV and TDF treatment groups were 2.78 (95% CI: 2.21-3.40) and 2.59 (95% CI: 1.51-3.96) per 100 persons-year among patients with preexisting cirrhosis and 0.49 (95% CI: 0.32-0.68) and 0.30 (95% CI: 0.06-0.70) per 100 persons-year among patients without preexisting cirrhosis. As the proportion of CHB patients with preexisting cirrhosis increased, the incidence density of HCC also increased gradually. Compared with other Nucleos(t)ide analogs (NAs) treatments, ETV and TDF treatments significantly lowered the risk of HCC, with hazard ratios (HRs) of 0.60 (95% CI: 0.40-0.90) and 0.56 (95% CI: 0.35-0.89), respectively. However, there was no difference in the incidence density of HCC between ETV and TDF treatments (HR = 0.92, 95% CI: 0.71-1.20) regardless of preexisting cirrhosis.

Conclusion: ETV and TDF treatments were associated with significantly lower risks of HCC than other NAs treatments. However, no difference was observed between ETV and TDF treatments in the risk of HCC development regardless of preexisting cirrhosis among treatment-naïve CHB patients.

Keywords: Chronic hepatitis B; Cirrhosis; Entecavir; Hepatocellular carcinoma; Tenofovir.

Fig. 1

Flow chart of the literature retrieval process

Fig. 2

Bubble charts of the cumulative incidence by different (A) median treatment duration and (B) the proportion of CHB patients with preexisting cirrhosis subgroups. Trend lines fitted linearly represent the predicted HCC incidence according to different treatments. ETV, Entecavir; TDF, Tenofovir disoproxil fumarate; Other NAs, Nucleos(t)ide Analogues other than ETV and TDF (including Lamivudine, Telbivudine and Adefovir). The bubble size represents the sample size for each study

Fig. 3

Bubble charts of incidence density according to preexisting cirrhosis proportion. Trend lines fitted linearly represent the predicted HCC incidence density according to different treatments. ETV, Entecavir; TDF, Tenofovir disoproxil fumarate; Other NAs, Nucleos(t)ide Analogues other than ETV and TDF (including Lamivudine, Telbivudine and Adefovir). The bubble size represents the sample size for each study

Fig. 4

Network plot and forest plots from the network meta-analysis of HCC risk in CHB patients receiving different treatments. A Results of the total analysis. B Results of the subgroup analysis of patients with cirrhosis. C Results of the subgroup analysis of patients without cirrhosis. Control, no treatment or expectant treatment; ETV, Entecavir treatment; TDF, Tenofovir disoproxil fumarate treatment; Other NAs, Nucleos(t)ide Analogue treatments other than ETV and TDF (including Lamivudine, Telbivudine and Adefovir)

Fig. 5

Pooled hazard ratio for HCC incidence between TDF and ETV treatments in CHB patients