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Perspective  |  Open Access  |  20 Mar 2022

Tenofovir disoproxil fumarate is not associated with a lower risk of hepatocellular carcinoma compared to entecavir in patients with chronic hepatitis B

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Hepatoma Res 2022;8:13.
10.20517/2394-5079.2021.114 |  © The Author(s) 2022.
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Abstract

A paper published several years ago suggested that tenofovir disoproxil fumarate (TDF) was superior to entecavir (ETV) for reducing the risk of hepatocellular carcinoma (HCC). Since then, many observational studies have been conducted comparing TDF and ETV. Many studies in Asia demonstrated similar HCC risks between ETV and TDF groups. Similarly, recent studies involving Caucasian and European did not observe any differences in HCC risk between these groups. In this article, we briefly review studies that compared the incidence rates of HCC between ETV and TDF and discuss potential reasons for the discrepant results.

Keywords

Hepatitis B, entecavir, tenofovir, hepatocellular carcinoma

INTRODUCTION

Hepatitis B virus (HBV) infection is a major cause of chronic liver disease worldwide. In the present era of potent antiviral therapy, entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are used to suppress HBV replication and prevent disease progression[1,2]. Although both antiviral agents reduce the hepatocellular carcinoma (HCC) risk compared to no antiviral treatment, it is not clear whether TDF is superior to ETV in terms of reducing the HCC risk in patients with chronic hepatitis B (CHB). No randomized clinical trials have yet been conducted on this topic. Instead, several observational studies have compared the effects of TDF and ETV in terms of the risk of HCC development. The studies, which have generated strong interest in this topic, are summarized in this article [Table 1].

Table 1

The summary of studies which were reviewed in this commentary

AuthorsCountryStudy designNumber of patientsHR (TDF vs. ETV)95%CI
Choi et al.[4]South KoreaRetrospective24,156 patients with CHB (administrative data) and 2701 patients with CHB (a tertiary hospital-based cohort)0.61*0.53-0.70
Choi et al.[5]South KoreaMeta-analysis16,101 patients with TDF and 45,686 patients with ETV0.80*0.69-0.93
Yip et al.[6]Hong KongRetrospective29,350 treatment-naïve CHB patients (1309 patients with TDF and 28,041 with ETV)0.36* (PS matching)
0.39* (1:5 matching)
0.16-0.80
0.18-1.84
Kim et al.[7]South KoreaRetrospectiveTDF (n = 1413) and ETV (n = 1484)1.021 (PS matching)
0.998 (IPTW)
Lee et al.[8]South KoreaRetrospectiveTDF (n = 1439) and ETV (n = 1583) 1.030.703-1.509
Oh et al.[9]South KoreaRetrospectiveTDF (n = 807) and ETV (n = 753)1.260.81-1.97
Tseng et al.[10]TaiwanMeta-analysis520 matched pairs of patients with TDF or ETV1.030.88-1.21
Papatheodoridis et al.[11]CaucasianRetrospectiveTDF (n = 1163) and ETV (n = 772)1.170.70-1.97
Pol[12]EuropeanRetrospective1800 patients (986 patients with TDF and 814 with ETV)1.24 (IPW analysis)
1.06 (Univariable)
1.51 (Multivariable)
0.49-3.13
0.45-2.52
1.51-3.92

Studies showing the superiority of TDF

Choi et al.[3] were the first to suggest that TDF is superior to ETV for reducing the risk of HCC development. Choi et al.[4] analysed two retrospective cohorts based on a large administrative data set (24,156 patients with CHB) and a tertiary hospital-based cohort (2701 patients with CHB). The risk for HCC was 39% lower in the TDF group compared to the ETV group [hazard ratio (HR) = 0.61; 95% confidence interval (CI): 0.53-0.70]. The difference remained statistically significant after adjustment for covariates. Patient’s compliance to antivirals and surveillance may differently affect the risk for HCC development. In addition, patients in the ETV group had greater primary exposure to lamivudine compared to the TDF group patients. Moreover, treatment was switched more frequently for the patients in the ETV group (12%) compared to the TDF group (0.2%).

Recently, the same group of researchers again reported a significantly lower risk of HCC in TDF compared to ETV (HR = 0.80; 95%CI: 0.69-0.93)[5]. This systematic review and meta-analysis included 15 studies (16,101 patients with TDF and 45,686 with ETV). Meta-regression analyses were used to explain between-study heterogeneity and the conflicting results of the included reports. Between-study heterogeneity in this meta-analysis was explained by differences in sample sizes, the ages of the participants, the proportions of patients with cirrhosis, and the inclusion criteria (e.g., inclusion of decompensated cirrhosis).

Another study, conducted in Hong Kong, demonstrated similar results. Yip et al.[6] observed a lower risk of HCC development with TDF than ETV treatment in 29,350 treatment-naïve CHB patients (1309 patients with TDF and 28,041 with ETV). To minimize selection bias, the researchers used various statistical methods, including propensity score matching and weighting, inverse probability of treatment weighting, and competitive risk analysis. There was a lower incidence of HCC among TDF than ETV patients after propensity score weighting (HR = 0.36; 95%CI: 0.16-0.80; P = 0.013) and 1:5 matching (HR = 0.39; 95%CI: 0.18-0.84; P = 0.016). However, the effects of confounders could not be eliminated despite the application of propensity score weighting and competitive risk analysis. In addition, as ETV was approved by the Food and Drug Administration prior to TDF, the TDF group included fewer patients and had a shorter follow-up period.

Studies showing no difference between ETV and TDF

In contrast, three studies from South Korea did not observe any differences in the risk of HCC development between TDF and ETV groups[7-9]. Most studies related to this topic has been conducted in East Asia.

Our group reported that the annual incidence of HCC did not differ between ETV-treated (n = 1484) and TDF-treated (n = 1413) patients (1.92 and 1.69/100 person-years, respectively; adjusted HR = 0.975)[7]. In that study, treatment-naïve CHB patients were recruited from four teaching hospitals and received either ETV or TDF as a first-line antiviral drug. Statistical methods yielded similar results in both propensity score-matching (HR = 1.021; P = 0.884) and inverse probability of treatment weighting analyses (HR = 0.998; P = 0.988). Long-term use of ETV did not increase the risk of HCC development.

Lee et al.[8] reported similar results for 7015 CHB patients. No differences were observed in the incidence of HCC between TDF and ETV groups (HR = 1.030; 95%CI: 0.703-1.509; P = 0.880 for the propensity score model) or in the subgroup of cirrhotic patients. Similarly, no differences were observed in the rates of all-cause mortality or liver transplantation between TDF-treated and ETV-treated patients in the entire cohort (HR = 1.090; 95%CI: 0.622-1.911; P = 0.763 for the propensity score model), or in the subgroup of CHB patients with cirrhosis.

Oh et al.[9] analysed data from 1560 treatment-naïve CHB. HCC was developed in 4.5% and 5.6% of ETV-treated (n = 753) and TDF-treated (n = 807) patients, respectively. There was no difference between the ETV and TDF groups (HR = 1.26; 95%CI: 0.81-1.97; P = 0.303). The cumulative incidence rates of HCC at 2, 3, 4, and 5 years were 1.3%, 3.2%, 4.0%, and 4.5% in the ETV group and 2.2%, 3.8%, 5.2%, and 5.5% in the TDF group, respectively. The differences in incidence rates between the groups remained statistically insignificant after propensity score matching.

Tseng et al.[10] included 31 studies and 119,053 patients in their systematic review and meta-analysis. The 5-year cumulative incidence rates of HCC were 5.97% (95%CI: 5.81-6.13) for ETV and 3.06% (95%CI: 2.86-3.26) for TDF in studies with unmatched populations (P < 0.0001). However, in studies matched by propensity scores, the 5-year cumulative incidence rates of HCC were 3.44% (95%CI: 3.08-3.80) for ETV and 3.39% (95%CI: 2.94-3.83) for TDF (P = 0.87). After adjustment for covariates in 14 comparative studies, the risk of HCC development was similar between TDF-treated and ETV-treated patients (adjusted HR = 0.88; 95%CI: 0.73-1.07; P = 0.20).

The data from Caucasian and European did not show any differences in the risk of HCC between ETV and TDF groups[11,12]. The 5-year cumulative incidence rates of HCC were not statistically different between CHB patients treated with ETV (n = 772) and TDF (n = 1163), at 5.4% and 6.0%, respectively (P = 0.321)[11]. In multivariate analyses, HCC risk was similar between the ETV and TDF groups (HR = 1.17; 95%CI: 0.70-1.97; P = 0.549) after adjustment for risk factors (age, smoking status, diabetes, alanine aminotransferase level, hepatitis B e-antigen level, antiviral therapy before ETV/TDF, and cirrhosis). European data also revealed a similar risk of HCC development between ETV- and TDF-treated patients with CHB (HR = 1.24; 95%CI: 0.49-3.13 in inverse probability weighting analysis, HR = 1.51; 95%CI: 0.58-3.92 in multivariate analysis)[12].

For the purpose of secondary prevention, the risks of HCC development between ETV and TDF are still controversial. TDF was associated with a lower risk of HCC recurrence after curative hepatectomy for HBV-related HCC[3]. Contrarily, ETV and TDF treatment did not show differ in terms of HCC recurrence after hepatic resection or radiofrequency ablation (HR = 0.932; P = 0.622)[13].

The reason for the discrepancies among studies is not clear. However, there are several possibilities[14]. First, many studies claiming superiority of TDF analysed big data, which may have imbalanced the HCC risk factors despite statistical matching. Second, patients with severe chronic liver disease tended to first receive ETV because it was approved earlier than TDF. Also, TDF may be toxic to bones and kidneys, biasing initial patient selection. Third, the meta-analysis included studies that lacked statistical significance or had very small numbers of patients. Fourth, interferon-lambda was suggested to mediate the anti-tumour effect of TDF, but there is no definitive in vitro or in vivo evidence that ETV is more carcinogenic than TDF. Lastly, TDF seemed to be associated with more frequent “elastographic reversion” of cirrhosis at year 5[15], but further studies are needed for validation

CONCLUSION

It is not clear whether TDF is superior to ETV for HCC prevention. Most observational studies have demonstrated similar HCC risk levels between ETV and TDF. Our published data also support the view that there is no difference between ETV and TDF in terms of the risk of HCC development. Because it is challenging to perform a prospective, randomized study to compare HCC risk between ETV and TDF, further well-designed comparisons are needed to confirm the best treatment for patients with CHB.

DECLARATIONS

Authors’ contributions

Writing: Lee HW, Kim SU

Supervision: Kim SU

Availability of data and materials

Not applicable.

Financial support and sponsorship

None.

Conflicts of interest

Both authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Copyright

© The Author(s) 2022.

REFERENCES

1. Wong GL, Chan HL, Mak CW, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology 2013;58:1537-47.

2. Liu K, Choi J, Le A, et al. Tenofovir disoproxil fumarate reduces hepatocellular carcinoma, decompensation and death in chronic hepatitis B patients with cirrhosis. Aliment Pharmacol Ther 2019;50:1037-48.

3. Choi J, Jo C, Lim YS. Tenofovir versus entecavir on recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. Hepatology 2021;73:661-73.

4. Choi J, Kim HJ, Lee J, Cho S, Ko MJ, Lim YS. Risk of hepatocellular carcinoma in patients treated with entecavir vs tenofovir for chronic hepatitis B: a Korean nationwide cohort study. JAMA Oncol 2019;5:30-6.

5. Choi WM, Choi J, Lim YS. Effects of tenofovir vs entecavir on risk of hepatocellular carcinoma in patients with chronic HBV infection: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2021;19:246-58.e9.

6. 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;158:215-25.e6.

7. Kim SU, Seo YS, Lee HA, et al. A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naïve chronic hepatitis B in South Korea. J Hepatol 2019;71:456-64.

8. Lee SW, Kwon JH, Lee HL, et al. Comparison of tenofovir and entecavir on the risk of hepatocellular carcinoma and mortality in treatment-naïve patients with chronic hepatitis B in Korea: a large-scale, propensity score analysis. Gut 2020;69:1301-8.

9. Oh H, Yoon EL, Jun DW, et al. Long-Term Safety of Entecavir and Tenofovir in Patients With Treatment-Naive Chronic Hepatitis B Virus (CHB) Infection (SAINT) Study. No difference in incidence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection treated with entecavir vs tenofovir. Clin Gastroenterol Hepatol 2020;18:2793-802.e6.

10. Tseng C, Hsu Y, Chen T, et al. Hepatocellular carcinoma incidence with tenofovir versus entecavir in chronic hepatitis B: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2020;5:1039-52.

11. Papatheodoridis GV, Dalekos GN, Idilman R, et al. Similar risk of hepatocellular carcinoma during long-term entecavir or tenofovir therapy in Caucasian patients with chronic hepatitis B. J Hepatol 2020;73:1037-45.

12. S; ANRS/AFEF study group. Similar 5-year HCC occurrence in Tenofovir- and Entecavir-treated HBV chronic infection in the French AFEF/ANRS CO22 Hepather cohort. Aliment Pharmacol Ther 2021;53:616-29.

13. Lee JH, Kim BK, Park SY, et al. The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma. Eur J Intern Med 2021;89:48-55.

14. Lee SW, Choi J, Kim SU, Lim YS. Entecavir versus tenofovir in patients with chronic hepatitis B: Enemies or partners in the prevention of hepatocellular carcinoma. Clin Mol Hepatol 2021;27:402-12.

15. Papatheodoridis G, Dalekos G, Yurtaydin S, et al. Prediction and need for surveillanceof hepatocellular carcinoma (HCC) development after the first 5 years of entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy in Caucasian chronic hepatitis B (CHB) patients of the PAGE-B cohort. 2018.

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OAE Style

Lee HW, Kim SU. Tenofovir disoproxil fumarate is not associated with a lower risk of hepatocellular carcinoma compared to entecavir in patients with chronic hepatitis B. Hepatoma Res 2022;8:13. http://dx.doi.org/10.20517/2394-5079.2021.114

AMA Style

Lee HW, Kim SU. Tenofovir disoproxil fumarate is not associated with a lower risk of hepatocellular carcinoma compared to entecavir in patients with chronic hepatitis B. Hepatoma Research. 2022; 8: 13. http://dx.doi.org/10.20517/2394-5079.2021.114

Chicago/Turabian Style

Lee, Hye Won, Seung Up Kim. 2022. "Tenofovir disoproxil fumarate is not associated with a lower risk of hepatocellular carcinoma compared to entecavir in patients with chronic hepatitis B" Hepatoma Research. 8: 13. http://dx.doi.org/10.20517/2394-5079.2021.114

ACS Style

Lee, HW.; Kim SU. Tenofovir disoproxil fumarate is not associated with a lower risk of hepatocellular carcinoma compared to entecavir in patients with chronic hepatitis B. Hepatoma. Res. 2022, 8, 13. http://dx.doi.org/10.20517/2394-5079.2021.114

About This Article

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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