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Effect of entecavir and tenofovir disoproxil fumarate on hepatocellular carcinoma in subjects with chronic hepatitis B: a meta-analysis

Beni-Suef University Journal of Basic and Applied Sciences volume 11, Article number: 114 (2022) Cite this article

Abstract

Background

A meta-analysis was made to assess the impact of entecavir comparison with tenofovir disoproxil fumarate as nucleos(t)ide analogue on hepatic cellular carcinoma (HCC). The study had subjects with chronic hepatitis B virus (HBV). Systemic research was done for all studies concerned with our topic till the date (March 2022). We included 19 studies in which 27,618 subjects participated. All subjects included were diagnosed with chronic HBV at the beginning of the study. A total of 15,734 subjects from the overall 27,618 were medicated with entecavir; however, 11,884 subjects were on tenofovir disoproxil fumarate. We calculated the odds ratio (OR) with confidence intervals (CIs) of 95% to evaluate the impact of entecavir and tenofovir disoproxil fumarate on HCC in subjects with chronic HBV by applying a dichotomous approach with a random or fixed-effect model.

Results

Chronic HBV subjects treated with entecavir showed a higher significant biochemical response than those treated with tenofovir disoproxil fumarate (OR 1.39; 95% CI 1.21–1.60, at p < 0.001). Also, no significant difference was detected with entecavir compared to tenofovir disoproxil fumarate concerning the occurrence of hepatic cells cancer (OR 1.26; 95% CI 0.96–1.67, p = 0.10), virological response (OR 0.89; 95% CI 0.63–1.25, p = 0.49), and seroconversion (OR 1.27; 95% CI 0.76–2.14, p = 0.37).

Conclusions

The use of entecavir resulted in a significantly higher biochemical response; nevertheless, it did not show any significant variation concerning the occurrence of hepatic cancer, virological response, or serological conversion compared to tenofovir disoproxil fumarate in chronic HBV subjects. So, results interpretation needs to be carried out carefully owing to the limited number of studies included in specific comparisons, e.g., serological conversion.

1 Background

Hepatic cancer is considered the third predominant reason for death cases related to cancer disease worldwide [1]. It also represents the second main reason for deaths resulting from cancer disease worldwide [2]. Hepatic cellular carcinoma (HCC) is considered the most prevalent hepatic cancer, representing approximately 90% of primary hepatic cancers [2]. Infection with chronic hepatitis B virus (HBV) represents the main risk factor for HCC [3]. The occurrence of HCC is the highest in regions where HBV infection is widespread. [4]. In current years, the increased accessibility to antiviral therapy and hepatitis B virus vaccines caused a decrease in the frequency of HBV infection throughout different areas [5], though in 2012, almost 300 million subjects were infected with chronic HBV [6]. Also, the percentages of immunized people against the hepatitis B virus in widespread regions did not elevate significantly from this year, except in South Asia [7]. Therefore, HCC caused by HCV remains a danger to public health in the world. Most chronic hepatitis B subjects are managed by using interferon of α type and/or a nucleotide, or nucleotide analogue [8]. Interferon stimulates the synthesis of hundred genes, enhancing the natural responsiveness of subject immunity against hepatic cells infected with HBV [9]. However, nowadays, analogues of nucleotides occur and proceed to inhibit the replication of HBV directly by stopping the process of reverse transcription of the virus [10]. Interferon implication in practical clinical aspects is not allowed till now, as it can cause serious adverse events that comprise hypolymphemia, leukopenia, thrombopenia, depression, and sleeplessness [11]. Undesired adverse events that result from applying analogues of nucleotide (nucleoside) are usually mild and rare [11]. Currently, nucleotide and nucleoside analogues approved for managing chronic HBV in the world include entecavir, tenofovir alafenamide, lamivudine, tenofovir disoproxil fumarate (adefovir dipivoxil), and (telbivudine). Both entecavir (C12H15N5O3) and tenofovir disoproxil fumarate (C23H34N5O14P) are selected from those previous drugs to be used as a first-line treatment due to limited detected hepatic cell resistance compared with the other analogues [11]. Continuous management with (nucleoside) and (nucleotide) analogues can postpone the clinical development of chronic HBV in subjects who developed cirrhosis and those who did not [12]. Though nucleos(t)ide analogues stop viral replication, they do not entirely eradicate the hepatitis B virus in numerous subjects [13]. Consequently, numerous chronic HBV subjects need prolonged antiviral management [11]. Clinical studies have reported that nucleos(t)ide analogue management also decreases the risk of HCC in chronic HBV subjects to different degrees [11, 14], though several studies have not shown significant differences among various nucleos(t)ide analogues about decreases in HCC frequency [15,16,17,18], excluding subjects who developed cirrhosis previously [15,16,17,18]. Comparing different studies concerning various nucleos(t)ide analogues is confusing, their management protocols, varieties in the study design, periods of investigation, and selection techniques [15]. Comparatively limited numbers of studies on a broad scale were done. Those studies assessed efficiencies of various nucleos(t)ide analogues for decreasing HCC risk, most of which were retrospective analyses with an essentially higher risk of selection bias than a prospective study or randomized control trial [19,20,21,22,23]. Also, several studies comparing the effectiveness of various nucleos(t)ide analogues for decreasing hepatocellular carcinoma frequency, comprising one randomized control trial [24], interpreted information gathered from comparatively limited samples [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. The small sample size may affect the statistical strength of the results. As prolonged management is recommended for numerous chronic HBV subjects, the selection of which nucleos(t)ide analogue to be used in such circumstances must include serological conversion, the therapeutic response of subjects for treatment of viruses, responding of viruses, renal toxicity, and nucleos(t)ide analogue resistance, features which have been extensively studied, though the comparative efficiencies of nucleos(t)ide analogues for a long-term decrease in hepatocellular carcinoma risk and the influence of cirrhosis on hepatocellular carcinoma outcomes concerning nucleos(t)ide analogue-treated chronic hepatitis B subjects are topics that have not been assessed carefully. To ease the evidence-based selection of nucleos(t)ide analogues for long-term antiviral management in chronic HBV subjects, we completed this meta-analysis to compare the efficacies of nucleos(t)ide analogues in chronic hepatitis B subjects. Consequently, we lead this meta-analysis study on the impact of entecavir compared with tenofovir disoproxil fumarate as nucleos(t)ide analogue on HCC in subjects with chronic HBV and studying their influence on different outcomes.

2 Method

2.1 Study design

The current meta-analysis included research regarding the declaration of epidemiology with a pre-established study protocol [34]. Numerous search engines were used to collect and analyze data, including OVID, Embase, PubMed, and Google Scholar databases.

2.2 Data pooling

Data were collected from randomized controlled trials, observational studies, and retrospective studies investigating the impact of entecavir compared with tenofovir disoproxil fumarate as nucleos(t)ide analogue on HCC in subjects with chronic HBV and studying their influence on different outcomes. Research studies carried out on humans in any language were only incorporated. Inclusion criteria were not affected by the sample size. Excluded research represented commentaries, review articles, and research that did not introduce association determination. The study procedure is represented clearly in Fig. 1. The studies were incorporated into this study of meta-analysis only if the inclusion criteria listed below were matched:

  1. 1.

    Study is either prospective, observational, randomized controlled, or retrospective.

  2. 2.

    Population concerned was subjects suffering from chronic HBV.

  3. 3.

    Protocol of intervention based on entecavir and tenofovir disoproxil fumarate.

  4. 4.

    The study included entecavir compared with tenofovir disoproxil fumarate

Fig. 1
figure 1

Diagram showing defined steps of the study

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The exclusion criteria were as follows:

  1. 1.

    Studies that lack clarification for influences of entecavir compared with tenofovir (disoproxil fumarate) on HCC in chronic HBV subjects

  2. 2.

    Studies with subjects treated with medication other than entecavir and tenofovir disoproxil fumarate as nucleos(t)ide analogue

  3. 3.

    Studies lack concentration on the effect of comparative results.

2.3 Identification

The system of search approaches were designed based on the PICOS concept [35]; it can be defined as P (population): chronic HBV subjects; I (intervention): entecavir; C (comparison): entecavir compared with tenofovir disoproxil; O (outcome): therapeutic effect, the occurrence of hepatocellular carcinoma, virological response, and transformation of serology; and S (design of the study): no limitation [36].

Initially, a systemic search was done in the following databases: OVID, PubMed, the library of Cochrane, Embase, and Google Scholar until March 2022. We searched by using keywords and similar words, including chronic HBV, entecavir, tenofovir disoproxil fumarate, virological response, serological conversion, hepatocellular carcinoma, and biochemical response as shown in Table 1. All included studies were gathered and put into a file of the EndNote program. Then, all duplications were excluded. Also, research abstracts and titles were reviewed to exclude studies that did not concentrate on the linkage between entecavir and tenofovir disoproxil fumarate in treating chronic HBV.

Table 1 Search strategy for each database
Full size table

2.4 Screening

Data have been curtailed based on the following criteria: properties concerning studies and subjects in a structured way; last name of the principal author, duration of research, year of publishing, country, area of research, and design of the study; type of population, subjects overall number, population information, medication properties, classifications, the qualitative and quantitative approach of assessment, source of information, and interpretation of results [37]. The data were retrieved from a single study when differences were found in the impact of entecavir compared to tenofovir disoproxil fumarate on HCC in HBV subjects. The possibility of bias occurrence in these studies was analyzed by employing two authors who separately evaluated the quality of methods used in the studies included. The tool (bias risk) from the Cochrane Guidebook concerned with intervention Systematic Reviews of Version (5.1.0) was utilized to evaluate the research methods' quality [38]. In terms of the assessment criteria, each study was rated and assigned to one of the following three risks of bias: low: if all quality criteria were met, the study was considered to have a low risk of bias; unclear: if one or more of the quality criteria were partially met or unclear, the study was considered to have a moderate risk of bias; or high: if one or more of the criteria were not met, or not included, the study was considered to have a high risk of bias. A reevaluation of the original article addressed any inconsistencies.

2.5 Eligibility

Principal results concentrated on evaluating the impact of entecavir in comparison with tenofovir disoproxil fumarate on HCC in chronic HBV subjects and interpreting entecavir in comparison with tenofovir disoproxil fumarate were isolated, to form a summary.

2.6 Inclusion

Only the publications comparing the effects of entecavir versus tenofovir disoproxil fumarate were considered for sensitivity analysis. Entecavir and tenofovir disoproxil fumarate were compared as nucleos(t)ide analogues in subclass and sensitivity analyses.

2.7 Statistical analysis

The odds ratio (OR) and 95% CI were calculated using the dichotomous technique with a random or fixed-effect model in this meta-analysis. I2 index ranged from 0 to 100% was measured. Values of 0%, 25%, 50%, and 75% indicated no, low, moderate, and high heterogeneity, respectively [39]. When I2 was greater than 50%, the random-effect model was used; when it was below 50%, the fixed-effect model was used. As previously explained, a subgroup analysis was accomplished by stratifying the initial evaluation for result categories. For the present analysis, a p value of 0.05 was found to be statistically significant concerning variations among subgroups. Egger regression test was used to assess bias in selection objectively (publication bias was deemed existent if p ≥ 0.05) and subjectively by looking at funnel graphs of the logs of ORs vs their standard errors (SE) [35]. The two-tailed test was used to calculate overall p values. Reviewer Manager version 5.3 was used to provide the statistical findings and graphs (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

3 Results

In total, 1045 relevant papers were screened. Only 19 studies in the period between the year 2013 and the year 2022 were included in this meta-analysis [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. Data obtained from these studies are shown in Table 2.

Table 2 Characteristics of the selected studies for the meta-analysis
Full size table

The selected studies included 27,618 subjects with HBV at the baseline of the studies; 15,734 were medicated with entecavir, and 11,884 used tenofovir disoproxil fumarate.

The number of participants was between 149 and 4956 subjects at the study's beginning. Ten studies revealed data concerning the biochemical response, 17 studies revealed results concerning the occurrence of hepatocellular carcinoma, 11 studies revealed results concerning virological response, and 3 studies revealed data concerning serological conversion.

The use of entecavir resulted in a significantly higher biochemical response in subjects with chronic HBV compared with tenofovir disoproxil fumarate (OR 1.39; 95% CI 1.21–1.60, p < 0.001) with moderate heterogeneity (I2 = 58%) as illustrated in Fig. 2. No significant difference was shown by entecavir concerning occurrence of HCC (OR 1.26; 95% CI 0.96–1.67, p = 0.10) with high heterogeneity (I2 = 83%), virological response (OR 0.89; 95% CI 0.63–1.25, p = 0.49) with high heterogeneity (I2 = 92%), and serologic transformation (OR 1.27; 95% CI 0.76–2.14, p = 0.37) with moderate heterogeneity (I2 = 55%) when compared to tenofovir disoproxil fumarate in subjects suffering chronic HBV as shown in Figs. 3, 4, and 5.

Fig. 2
figure 2

Difference between the impact of entecavir and tenofovir disoproxil concerning results of biochemical response in chronic HBV subjects

Full size image
Fig. 3
figure 3

Difference between the impact of entecavir and tenofovir disoproxil concerning HCC occurrence in chronic HBV subjects

Full size image
Fig. 4
figure 4

Difference between the impact of entecavir and tenofovir disoproxil concerning the results of virological responses in chronic HBV subjects

Full size image
Fig. 5
figure 5

Difference between the impact of entecavir and tenofovir disoproxil concerning results of seroconversion in chronic HBV subjects

Full size image

Individualized variables such as age, race, and sex were not adjusted into stratified models to explore their effect on comparison outcomes because no data were available on these variables. Furthermore, a visual check of the distribution curve and quantitative variables using Egger regression analysis revealed no proof of selection bias (p = 0.87). Nevertheless, most of the papers used in the study had poor method quality, slight selective publication bias, insufficient results, and biased reporting.

4 Discussion

The current meta-analysis involved 19 studies recruiting 27,618 subjects suffering from chronic HBV at the baseline of studies; 15,734 were medicated using entecavir. Also, 11,884 used tenofovir disoproxil fumarate [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]. The use of entecavir resulted in a significantly higher biochemical response in subjects having chronic HBV compared to tenofovir disoproxil fumarate. However, entecavir did not show any significant variation in HCC, virological response, and serological conversion occurrence compared with tenofovir disoproxil fumarate in subjects with chronic HBV. This insignificance difference suggests further additional research to assess these results. However, high p values in virological response and serological conversion revealed that more studies would not affect the detected nonsignificant difference. So, interpretation of resulted data should be made carefully owing to the limited number of studies available, e.g., serological conversion.

All nucleos(t)ide analogues used for treating chronic HBV bind to the enzyme DNA polymerase of HBV competitively. This holds the reversed transcription process of the virus and hinders the reproduction (replication) process of the virus, though nucleos(t)ide analogues do not affect HBV circular DNA bonds. As a result, viral DNA conserves its stability and remains stable inside hepatic cell nuclei for prolonged periods [40]. HBV levels are elevated significantly if nucleos(t)ide analogue medication is ceased before DNA polymerase of the virus is inhibited or destroyed by revenue of cellular protein because the single-stranded circular DNA is being used as a pattern to generate viral transcripts, which then function as templates for the initial reverse transcription process. [41] Consequently, reaching targeted chronic hepatitis B, clinical result demands HBV replication inhibition for long periods. Stopping the development of hepatic cirrhosis and hepatocellular carcinoma is an essential therapeutic objective, which are essentially connected to inhibiting the virus. Though various nucleos(t)ide analogues have similar effects on hepatocellular carcinoma, progress is not clear, and cirrhosis effect on the protective nucleos(t)ide analogues medications has not been sufficiently considered. Present guidelines for chronic HBV management suggest entecavir and tenofovir disoproxil fumarate as first-line therapy [42]. The rate of medication tolerance found for different nucleos(t)ide derivatives drives these recommendations. The decline of hepatitis B virus suppression and development of resistance to such nucleos(t)ide analogues necessitate a rescue medication that includes either entecavir or tenofovir disoproxil fumarate [42]. Despite entecavir tolerance being uncommon, some viral modifications that give lamivudine or telbivudine tolerance may also elevate the probability of entecavir tolerance [43]. Concerning selecting the best nucleos(t)ide analogue for decreasing the risk of HCC, no significant difference was found between entecavir and tenofovir disoproxil fumarate monotherapy. Resistance prevention is required to achieve prolonged inhibition of HBV replication. The research concluded that tenofovir disoproxil fumarate alone was cheaper than other nucleos(t)ide analogues for treating chronic HBV based on average yearly and entire life illness expenses for each subject, lifelong expenses and life expectancy, and quality-adjusted life year [44]. However, further study revealed that lamivudine + adefovir dipivoxil was nearly equivalent to tenofovir disoproxil [45]. Except for rescuing medication following the start of medication tolerance, no guidelines or recommendations concerning using a mix of various nucleos(t)ide analogues are currently present [11]. Nucleos(t)ide analogue treatment against the virus is found to be the cause of reducing the hazard of HCC indirectly by reducing DNA load of HBV and enhancing hepatic inflammatory response, and also throughout stimulating HBeAg seroconversion. Earlier studies show that nucleos(t)ide analogues can stop cirrhosis deterioration histologically and reduce the ratio of HCC by stopping virus replication. Many studies reported that hepatocellular carcinoma could progress into chronic hepatitis B subjects even with effective hepatitis B virus suppression [45,46,47]. Our results show that the decrease in risk of HCC was found to be statistically equivalent when the comparison is held between entecavir and tenofovir disoproxil fumarate (p > 0.05). Entecavir might be favored over tenofovir disoproxil fumarate because of the greater possibilities of tenofovir disoproxil fumarate for undesired side effects, and perhaps because physicians obtained a more significant experience concerning using entecavir because it was approved for chronic hepatitis B management in 2005, whereas tenofovir disoproxil fumarate use started in 2008.

This meta-analysis showed the influence of entecavir compared with tenofovir disoproxil fumarate on HCC in the case of chronic HBV subjects. Additional research is required to illustrate these correlations and compare the impact of entecavir and tenofovir disoproxil fumarate on the variables studied. Larger, more consistent samples are required for more significant results. This was also revealed in a prior meta-analysis study that found entecavir to have comparable encouraging results in treating HCC [48,49,50,51,52,53,54,55,56]. Because current meta-analysis cannot explain if various ages, races, and sex are linked with the findings, well-conducted randomized clinical trials are needed to investigate these parameters and the combination of various ages, ethnicity, and other variables of individuals.

In summary, the findings showed that entecavir produced a much stronger biochemical response in chronic HBV subjects than tenofovir disoproxil fumarate. In participants with chronic HBV, however, there was no significant difference in the prevalence of virological response, HCC, or serological transformation when entecavir was tested against tenofovir disoproxil fumarate.

4.1 Limitations

Bias may have occurred in the selection process of this review study as a high number of studies were not included in this meta-analysis study. In addition, a high number of ignored studies failed to fulfill the criteria of inclusion previously mentioned. Additionally, this review did not determine if there was a linkage between our results and the subjects' age, race, and sex. The study was designed to evaluate the impact of entecavir compared to tenofovir disoproxil fumarate on HCC in chronic HBV subjects. Also, it relied on results collected from studies carried out previously. This can result in bias caused by insufficient detailed information. Factors probably resulted in bias incorporated variables like age, gender, and subjects' status of nutrition.

5 Conclusions

The use of entecavir resulted in a significantly higher biochemical response; nevertheless, it did not show any significant variation concerning the occurrence of hepatic cancer, virological response, or serological conversion compared to tenofovir disoproxil fumarate in chronic HBV subjects, though results interpretation needs to be carried out carefully owing to the limited number of studies included in specific comparisons, e.g., serological conversion. This insignificance difference suggests further additional research to assess these results. Well-conducted randomized clinical trials are also needed to investigate these parameters and the combination of various ages, ethnicity, and other variables of individuals.

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

OR:

Odd ratio

CIs:

Confidence intervals

HCC:

Hepatic cellular carcinoma

HBV:

Chronic hepatitis B virus

References

  1. Xia C, Dong X, Li H, Cao M, Sun D, He S et al (2022) Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J 135(05):584–590

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249

    Article  PubMed  Google Scholar 

  3. Kew MC (2015) Epidemiology of hepatocellular carcinoma in sub-Saharan Africa. Ann Hepatol 12(2):173–182

    Article  Google Scholar 

  4. Control, C.f.D. and Prevention (2001) Health information for international travel 2001–2002. International Medical Pub

  5. Cui Y, Jia J (2013) Update on epidemiology of hepatitis B and C in C hina. J Gastroenterol Hepatol 28:7–10

    Article  PubMed  Google Scholar 

  6. Levrero M, Zucman-Rossi J (2016) Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol 64(1):S84–S101

    Article  CAS  PubMed  Google Scholar 

  7. Sohn W, Cho J-Y, Kim JH, Lee JI, Kim HJ, Woo M-A et al (2017) Risk score model for the development of hepatocellular carcinoma in treatment-naive patients receiving oral antiviral treatment for chronic hepatitis B. Clin Mol Hepatol 23(2):170

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tang LS, Covert E, Wilson E, Kottilil S (2018) Chronic hepatitis B infection: a review. JAMA 319(17):1802–1813

    Article  CAS  PubMed  Google Scholar 

  9. Schoggins JW, Rice CM (2011) Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol 1(6):519–525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Clark DN, Hu J (2015) Hepatitis B virus reverse transcriptase-target of current antiviral therapy and future drug development. Antiviral Res 123:132–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Terrault NA, Bzowej NH, Chang K-M, Hwang JP, Jonas MM, Murad MH (2016) AASLD guidelines for treatment of chronic hepatitis B. Hepatology 63(1):261

    Article  PubMed  Google Scholar 

  12. Niro G, Ippolito A, Fontana R, Valvano M, Gioffreda D, Iacobellis A et al (2013) Long-term outcome of hepatitis B virus-related C hronic H epatitis under protracted nucleos(t)ide analogues. J Viral Hepat 20(7):502–509

    Article  CAS  PubMed  Google Scholar 

  13. Wong GH, Tse YK, Yip TF, Chan HY, Tsoi KF, Wong VS (2017) Long-term use of oral nucleos (t) ide analogues for chronic hepatitis B does not increase cancer risk—a cohort study of 44 494 subjects. Aliment Pharmacol Therap 45(9):1213–1224

    Article  CAS  Google Scholar 

  14. Yin J, Li N, Han Y, Xue J, Deng Y, Shi J et al (2013) Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 31(29):3647–3655

    Article  CAS  PubMed  Google Scholar 

  15. Köklü S, Tuna Y, Gülşen MT, Demir M, Köksal AŞ, Koçkar MC et al (2013) Long-term efficacy and safety of lamivudine, entecavir, and tenofovir for treatment of hepatitis B virus-related cirrhosis. Clin Gastroenterol Hepatol 11(1):88–94

    Article  PubMed  CAS  Google Scholar 

  16. Tsai M-C, Chen C-H, Hung C-H, Lee C-M, Chiu K-W, Wang J-H et al (2014) A comparison of efficacy and safety of 2-year telbivudine and entecavir treatment in patients with chronic hepatitis B: a match–control study. Clin Microbiol Infect 20(2):O90–O100

    Article  CAS  PubMed  Google Scholar 

  17. Coffin C, Rezaeeaval M, Pang J, Alcantara L, Klein P, Burak K et al (2014) The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos (t) ide analogue therapy. Aliment Pharmacol Therap 40(11–12):1262–1269

    Article  CAS  Google Scholar 

  18. Idilman R, Gunsar F, Koruk M, Keskin O, Meral CE, Gulsen M et al (2015) Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-naïve chronic hepatitis B patients in the real-world setting. J Viral Hepat 22(5):504–510

    Article  CAS  PubMed  Google Scholar 

  19. Su F, Berry K, Ioannou GN (2021) No difference in hepatocellular carcinoma risk between chronic hepatitis B patients treated with entecavir versus tenofovir. Gut 70(2):370–378

    CAS  PubMed  Google Scholar 

  20. Shin JW, Jeong J, Jung SW, Lee SB, Park BR, Kim M-J et al (2021) Comparable incidence of hepatocellular carcinoma in chronic hepatitis B patients treated with entecavir or tenofovir. Dig Dis Sci 66(5):1739–1750

    Article  CAS  PubMed  Google Scholar 

  21. Na JE, Sinn DH, Lee JH, Jang HJ, Baek SY, Kim KA et al (2021) Efficacy of entecavir versus tenofovir in preventing hepatocellular carcinoma in patients with chronic hepatitis B with maintained virologic response. J Viral Hepat 28(10):1392–1399

    Article  CAS  PubMed  Google Scholar 

  22. Wang X-H, Hu Z-L, Fu Y-Z, Hou J-Y, Li W-X, Zhang Y-J et al (2022) Tenofovir vs. entecavir on prognosis of hepatitis B virus-related hepatocellular carcinoma after curative resection. J Gastroenterol 57(3):185–198

    Article  CAS  PubMed  Google Scholar 

  23. Jeong S, Shin HP, Kim HI (2022) Real-world single-center comparison of the safety and efficacy of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide in patients with chronic hepatitis B. Intervirology 65(2):94–103

    Article  CAS  PubMed  Google Scholar 

  24. Papatheodoridis GV, Dalekos GN, Idilman R, Sypsa V, Van Boemmel F, Buti M et al (2020) Similar risk of hepatocellular carcinoma during long-term entecavir or tenofovir therapy in Caucasian patients with chronic hepatitis B. J Hepatol 73(5):1037–1045

    Article  CAS  PubMed  Google Scholar 

  25. Riveiro-Barciela M, Tabernero D, Calleja JL, Lens S, Manzano ML, Rodríguez FG et al (2017) Effectiveness and safety of entecavir or tenofovir in a Spanish cohort of chronic hepatitis B patients: validation of the page-B score to predict hepatocellular carcinoma. Dig Dis Sci 62(3):784–793

    Article  CAS  PubMed  Google Scholar 

  26. Kim BG, Park NH, Lee SB, Lee H, Lee BU, Park JH et al (2018) Mortality, liver transplantation and hepatic complications in patients with treatment-naïve chronic hepatitis B treated with entecavir vs tenofovir. J Viral Hepat 25(12):1565–1575

    Article  CAS  PubMed  Google Scholar 

  27. Choi J, Kim HJ, Lee J, Cho S, Ko MJ, Lim Y-S (2019) Risk of hepatocellular carcinoma in patients treated with entecavir vs tenofovir for chronic hepatitis B: a Korean nationwide cohort study. JAMA Oncol 5(1):30–36

    Article  PubMed  Google Scholar 

  28. Oh H, Yoon EL, Jun DW, Ahn SB, Lee H-Y, Jeong JY et al (2020) No difference in incidence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection treated with entecavir vs tenofovir. Clin Gastroenterol Hepatol 18(12):2793–2802

    Article  CAS  PubMed  Google Scholar 

  29. Lee SW, Kwon JH, Lee HL, Yoo SH, Nam HC, Sung PS et al (2020) 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 69(7):1301–1308

    Article  CAS  PubMed  Google Scholar 

  30. Chen C-H, Chen C-Y, Wang J-H, Lai H-C, Hung C-H, Lu S-N et al (2020) Comparison of incidence of hepatocellular carcinoma between chronic hepatitis B patients with cirrhosis treated with entecavir or tenofovir in Taiwan-a retrospective study. Am J Cancer Res 10(11):3882

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Ha I, Chung JW, Jang ES, Jeong S-H, Kim J-W (2020) Comparison of the on-treatment risks for hepatocellular carcinoma between entecavir and tenofovir: a propensity score matching analysis. J Gastroenterol Hepatol 35(10):1774–1781

    Article  PubMed  Google Scholar 

  32. Chang T-S, Yang Y-H, Chen W-M, Shen C-H, Tung S-Y, Yen C-W et al (2021) Long-term risk of primary liver cancers in entecavir versus tenofovir treatment for chronic hepatitis B. Sci Rep 11(1):1–14

    CAS  Google Scholar 

  33. Lee JH, Kim BK, Park SY, Tak WY, Park JY, Ahn SH et al (2021) 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 89:48–55

    Article  CAS  PubMed  Google Scholar 

  34. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 283(15):2008–2012

    Article  CAS  PubMed  Google Scholar 

  35. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560

    Article  PubMed  PubMed Central  Google Scholar 

  36. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62(10):e1–e34

    Article  PubMed  Google Scholar 

  37. Gupta A, Das A, Majumder K, Arora N, Mayo HG, Singh PP et al (2018) Obesity is independently associated with increased risk of hepatocellular cancer-related mortality. Am J Clin Oncol 41(9):874–881

    Article  PubMed  PubMed Central  Google Scholar 

  38. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sheikhbahaei S, Trahan TJ, Xiao J, Taghipour M, Mena E, Connolly RM et al (2016) FDG-PET/CT and MRI for evaluation of pathologic response to neoadjuvant chemotherapy in patients with breast cancer: a meta-analysis of diagnostic accuracy studies. Oncologist 21(8):931–939

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Nassal M (2015) HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64(12):1972–1984

    Article  CAS  PubMed  Google Scholar 

  41. Wong DK-H, Seto W-K, Fung J, Ip P, Huang F-Y, Lai C-L et al (2013) Reduction of hepatitis B surface antigen and covalently closed circular DNA by nucleos(t)ide analogues of different potency. Clin Gastroenterol Hepatol 11(8):1004–1010

    Article  CAS  PubMed  Google Scholar 

  42. Terrault NA, Lok AS, McMahon BJ, Chang KM, Hwang JP, Jonas MM et al (2018) Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67(4):1560–1599

    Article  PubMed  Google Scholar 

  43. Liver, E.A.F.T.S.O.T. (2012) EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 57(1):167–185

    Article  Google Scholar 

  44. Buti M, Brosa M, Casado MA, Rueda M, Esteban R (2009) Modeling the cost-effectiveness of different oral antiviral therapies in patients with chronic hepatitis B. J Hepatol 51(4):640–646

    Article  CAS  PubMed  Google Scholar 

  45. Jayakumar R, Joshi YK, Singh S (2012) Laboratory evaluation of three regimens of treatment of chronic hepatitis B: tenofovir, entecavir and combination of lamivudine and adefovir. J Lab Phys 4(01):010–016

    CAS  Google Scholar 

  46. Honda M, Shirasaki T, Terashima T, Kawaguchi K, Nakamura M, Oishi N et al (2016) Hepatitis B virus (HBV) core-related antigen during nucleos (t) ide analog therapy is related to intra-hepatic HBV replication and development of hepatocellular carcinoma. J Infect Dis 213(7):1096–1106

    Article  CAS  PubMed  Google Scholar 

  47. Wong GH, Tse YK, Chan HY, Yip TF, Tsoi KF, Wong VS (2016) Oral nucleos (t) ide analogues reduce recurrence and death in chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Therap 43(7):802–813

    Article  CAS  Google Scholar 

  48. Yuan J, Peng Y, Hao F-B, Wang Y-Q, Wang C-R, Zhong G-C (2021) No difference in hepatocellular carcinoma risk in chronic hepatitis B patients treated with tenofovir vs entecavir: evidence from an updated meta-analysis. Aging 13(5):7147

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tseng C-H, Hsu Y-C, Chen T-H, Ji F, Chen I-S, Tsai Y-N et al (2020) Hepatocellular carcinoma incidence with tenofovir versus entecavir in chronic hepatitis B: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 5(12):1039–1052

    Article  PubMed  Google Scholar 

  50. Con D, Goodwin T, Majeed A, Roberts S, Kemp W (2021) Comparison of 48-week efficacy of tenofovir vs entecavir for patients with chronic hepatitis B: a network meta-analysis. J Viral Hepat 28(1):40–50

    Article  CAS  PubMed  Google Scholar 

  51. Geng J, Bao H, Chen Y, Shi L, Geng J, Wang Q et al (2020) Nucleos(t)ide analogues for the treatment of chronic hepatitis B: a systematic review with network meta-analysis. Expert Rev Anti-infect Ther 18(8):823–834

    Article  CAS  PubMed  Google Scholar 

  52. Liu H, Shi Y, Hayden JC, Ryan PM, Rahmani J, Yu G (2020) Tenofovir treatment has lower risk of hepatocellular carcinoma than entecavir treatment in patients with chronic hepatitis B: a systematic review and meta-analysis. Liver Cancer 9(4):468–476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gu L, Yao Q, Shen Z, He Y, Ng DM, Yang T et al (2020) Comparison of tenofovir versus entecavir on reducing incidence of hepatocellular carcinoma in chronic hepatitis B patients: A systematic review and meta-analysis. J Gastroenterol Hepatol 35(9):1467–1476

    Article  CAS  PubMed  Google Scholar 

  54. Choi W-M, Choi J, Lim Y-S (2021) 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 19(2):246–258

    Article  CAS  PubMed  Google Scholar 

  55. Wang X, Liu X, Dang Z, Yu L, Jiang Y, Wang X et al (2020) Nucleos (t) ide analogues for reducing hepatocellular carcinoma in chronic hepatitis B patients: a systematic review and meta-analysis. Gut Liver 14(2):232

    Article  CAS  PubMed  Google Scholar 

  56. Huang Z-H, Lu G-Y, Qiu L-X, Zhong G-H, Huang Y, Yao X-M et al (2022) Risk of hepatocellular carcinoma in antiviral treatment-naïve chronic hepatitis B patients treated with entecavir or tenofovir disoproxil fumarate: a network meta-analysis. BMC Cancer 22(1):1–12

    Article  CAS  Google Scholar 

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Acknowledgements

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Funding

There was no external funding for this study itself. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

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Authors and Affiliations

  1. Beni-Suef Specialized Hospital, Beni-Suef, Egypt

    Sara M. Tony

  2. Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt

    Mohamed E. A. Shaaban & Ahmed I. M. Mohamed

  3. Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt

    Mohamed E. A. Abdelrahim

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  1. Sara M. Tony
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  2. Mohamed E. A. Shaaban
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  3. Ahmed I. M. Mohamed
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  4. Mohamed E. A. Abdelrahim
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Contributions

Conception and design: MA. Administrative support: ST, ME, AM and MA. Provision of study materials: ST, ME, AM and MA. Collection and assembly of data: ME. Data analysis and interpretation: MA. Manuscript writing: MA. Final approval of manuscript: ST, ME, AM and MA. All authors read and approved the manuscript.

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Correspondence to Mohamed E. A. Abdelrahim.

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Tony, S.M., Shaaban, M.E.A., Mohamed, A.I.M. et al. Effect of entecavir and tenofovir disoproxil fumarate on hepatocellular carcinoma in subjects with chronic hepatitis B: a meta-analysis. Beni-Suef Univ J Basic Appl Sci 11, 114 (2022). https://doi.org/10.1186/s43088-022-00294-0

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  • DOI: https://doi.org/10.1186/s43088-022-00294-0

Keywords

  • Chronic hepatitis B virus
  • Entecavir
  • Tenofovir disoproxil fumarate
  • Virological response
  • Serological conversion
  • Hepatocellular carcinoma
  • Biochemical response