Background: Long-term therapy with nucleos(t)ide analogs (NAs) such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF) favorably affects the incidence of hepatocellular carcinoma (HCC) on the basis of data from randomized or matched control studies. Recent data suggest a lower HCC incidence after 5 years of ETV or TDF therapy in chronic hepatitis B (CHB) patients, especially those with baseline cirrhosis. Summary: Three controversial issues remain to be resolved regarding hepatitis B virus (HBV) treatment and HCC. (1) The efficacy of antiviral treatment for the prevention of HCC is not established. The guidelines of the American Association for the Study of Liver Diseases (AASLD), the Asian Pacific Association for the Study of the Liver (APASL), and the European Association for the Study of the Liver (EASL) for the management of HBV infection state that antiviral treatment of HBV with interferon and NAs prevents the development of HCC. Among experts in CHB treatment, however, there is disagreement on the HCC prevention effects of antiviral treatment. (2) The rationale for antiviral management in patients with high HBV DNA and normal levels of alanine aminotransferase is unclear. The AASLD, EASL, and APASL guidelines do not recommend antiviral treatment for immune-tolerant CHB patients, and the terms and methods of treating such patients remain to be clarified. (3) The efficacy of first-line treatment with NAs, including ETV, TDF, and tenofovir alafenamide fumarate (TAF), to prevent HCC in CHB patients remains unknown. Several studies have produced controversial results regarding the effects of NAs on the risk and prevention of HCC. In the present review, we discuss these 3 issues, citing recent studies and clinical management guidelines from major international associations. Key Messages: Suggested approaches for reaching a consensus including applying the propensity score matching method, performing randomized controlled studies, and performing clinical studies with larger numbers of subjects and longer follow-up.

Chronic hepatitis B (CHB) is the most common cause of hepatocellular carcinoma (HCC) and the second leading cause of cancer-related mortality worldwide [1, 2]. Global deaths from HCC attributed to hepatitis B virus (HBV) are projected to double by 2040 [1-3]. Analysis of randomized or matched control studies indicates that long-term therapy with nucleos(t)ide analogs (NAs), such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF), reduces the incidence of HCC [4-6].

Recent data suggest that 5 years of ETV or TDF therapy reduces the incidence of HCC in CHB patients, especially those with baseline cirrhosis [4, 6]. Nonetheless, the following 3 controversial issues regarding HBV treatment and the incidence of HCC remain to be resolved.

1.The efficacy of antiviral treatment for the prevention of HCC is not established.

Guidelines of the American Association for the Study of Liver Diseases (AASLD) [7], the Asian Pacific Association for the Study of the Liver (APASL) [8], and the European Association for the Study of the Liver (EASL) [4] for the management of HBV infection recommend antiviral treatment for HBV with interferon (IFN) and NAs for the prevention of HCC. Among experts in CHB treatment, however, there is disagreement on the HCC prevention effects of antiviral treatment.

2.The rationale for antiviral treatment of patients harboring high HBV DNA and normal alanine aminotransferase levels is not yet clear.

AASLD, EASL, and APASL guidelines have not reached a consensus regarding the efficacy of treatment during the immune-tolerant phase. Although positive hepatitis B e antigen (HBeAg), high serum HBV DNA, and normal alanine aminotransferase (ALT) levels are 3 key features of this phase, the guidelines do not currently recommend antiviral treatment for immune-tolerant CHB patients.

Further, the correlation between very high HBV DNA levels (especially >6 log10 IU/mL) and risk of HCC remains unclear, especially in middle-aged and older HBeAg-positive patients with normal ALT levels [1, 9]. Thus, the terms and methods of treating CHB patients with high levels of HBV DNA and normal levels of ALT in the immune-tolerant phase must be clarified.

3.The efficacy of first-line NAs, including ETV, TDF, and tenofovir alafenamide fumarate, for CHB patients to prevent HCC remains unclear.

ETV, TDF, and tenofovir alafenamide fumarate (TAF) in the AASLD and EASL clinical practice guidelines [4, 7], and ETV and TDF in the APASL clinical practice guidelines are recommended as first-line NAs for CHB because of their comparable high antiviral efficacy and low rate of resistance [8]. The results of several studies of ETV, TDF and TAF administration, however, have raised questions regarding the risk of HCC. To date, no studies have provided clear evidence regarding the potential HCC prevention effects of ETV, TDF, and TAF administration [10-16]. In the present review, we address these 3 issues and cite recent studies on HBV treatment and HCC prevention with reference to AASLD, EASL, and APASL guidelines for the management of HBV infection and suggest approaches for reaching a consensus.

Regarding the efficacy of antiviral treatment for HBV with IFN and NAs, the AASLD 2018 guidelines for the management of HBV infection state that, as for any patient with CHB, the treatment goals are to reduce the risk of progression to cirrhosis- and liver-related complications, including HCC. The APASL 2016 guidelines for the management of HBV infection state that the risk of CHB progressing to HCC may be reduced by antiviral therapy and recommend liver biopsy for noncirrhotic patients with a family history of HCC as well as treatment for moderate to severe inflammation or significant fibrosis.

The EASL guidelines for the management of HBV infection recommend treatment with NAs for the prevention of HCC in CHB patients [4, 6] on the basis of a European study (Table 1). A European 10-center cohort study of 1,951 adult Caucasian CHB patients (cirrhosis 201, 27%) without HCC at baseline received ETV/TDF for ≥1 year; 1,205 (62%) patients without HCC within the first 5 years of therapy were followed up for 5–10 (median, 6.8) years. HCC was diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5–10 years, demonstrating that the HCC risk decreases with ETV/TDF therapy beyond year 5, particularly in those with compensated cirrhosis, older age (especially ≥50 years), lower platelet counts, and liver stiffness ≥12 kPa [6] (Table 2).

Table 1.

Comparison of major international guidelines for the management of HBV

Comparison of major international guidelines for the management of HBV
Comparison of major international guidelines for the management of HBV
Table 2.

Representative remarks on the prevention of HCC with NAs

Representative remarks on the prevention of HCC with NAs
Representative remarks on the prevention of HCC with NAs

The AASLD [17], EASL [18], and APASL [19] guidelines for the management of HCC all recommend antiviral therapy for HBV patients to reduce the risk of HCC. Among experts in the treatment of CHB, however, there is controversy regarding antiviral HBV treatment for the prevention of HCC.

The achievement of HBsAg seroclearance during NA treatment is closely associated with improved clinical outcomes and is a criterion for the safe discontinuation of therapy [20]. HBsAg seroclearance is rarely, if ever, achievable, however, and necessitates long-term (almost indefinite) NA therapy for most patients with CHB. In the absence of HBsAg seroclearance, HCC can occur even during long-term continuous treatment with highly potent NAs [21-24].

A virologic response is defined as serum HBV DNA <15 IU/mL at 1 year of treatment for CHB or the achievement of a sustained virologic response for chronic hepatitis C (CHC). Kim et al. [23] reported that a virologic response was achieved in 1,520 patients with CHB (76.0%) and 475 patients with CHC (64.8%). During the median follow-up period of 6 years, 228 patients with CHB (11.4%) and 59 patients with CHC (8.0%) developed HCC. Among patients with virologic response, CHB was independently associated with a significantly higher incidence of HCC (hazard ratio [HR] 2.17; 95% confidence interval [CI] 1.30–3.63; p = 0.003) compared with CHC.

This does not mean cure, however, and does not address the reason for the persistent risk of HCC in CHB patients with a virologic response [23]. A positive outcome of antiviral treatment with NAs for the prevention of HCC was described in 651 randomly assigned patients having CHB with histologically confirmed cirrhosis or advanced fibrosis (98% Asian and 85% male) receiving lamivudine (LAM) or placebo. HCC occurred in 3.9% of the LAM group (n = 436) and 7.4% of the placebo group (n = 215; HR 0.49, p = 0.047; Table 2) [25].

A comparison between 482 ETV-treated and 69 untreated (control group) HBV-related cirrhosis patients (total of 551) revealed that ETV treatment reduced the risk of HCC (propensity score matching: HR 0.55, 95% CI: 0.31–0.99, p = 0.049; Table 2) [26]. In a comparison of the incidence of HCC in 472 ETV-treated (cirrhosis 311, 19.2%) and 1,143 untreated HBV patients (cirrhosis 195, 12.1%), propensity score matching eliminated baseline differences, resulting in a sample size of 316 patients per cohort. The cumulative HCC incidence rate at 5 years was 3.7% and 13.7% in the ETV and control groups, respectively (p < 0.001). Cox proportional hazard regression analysis adjusted for a number of known HCC risk factors showed that patients in the ETV group were less likely to develop HCC than those in the control group (HR 0.37, 95% CI: 0.15–0.91, p < 0.001; Table 2), leading to the conclusion that long-term ETV treatment reduces the incidence of HCC in HBV-infected patients [27].

A comparison by propensity score matching between 21,595 ETV-treated (cirrhosis 2,847, 13.2%) and 21,595 untreated CHB patients (cirrhosis 3,016, 14.0%) demonstrated that the incidence of HCC was significantly lower in the treated cohort over a 7-year follow-up (7.32%, 95% CI: 6.77–7.87) than in the control (22.7%, 95% CI: 22.1–23.3, p < 0.001; Table 2) [28]. Another study comparing between 1,315 ETV-treated cirrhosis patients and 503 untreated HBV-related cirrhosis patients concluded that ETV therapy was associated with a 60% lower risk of HCC incidence (HR 0.40, 95% CI: 0.28–0.57; Table 2) [29]. Even with successful treatment using antivirals, the risk of HCC is not eliminated and surveillance for HCC should continue in persons who are at risk.

To evaluate whether NA therapy prevents HCC in HBV patients, a population-based analysis of mortality from liver disease and liver cancer from 1999 to 2013 was implemented using data obtained from the national death certificate database of Korea, an HBV-endemic country. In terms of liver disease, the number of annual deaths decreased by 62.3% (95% CI: 62.0–62.6) and the crude death rate decreased by 64.6% (95% CI: 64.3–64.9) from 21.2 to 7.5 per 100,000 population; the age-standardized death rate also declined by 75.0% (95% CI: 74.7–75.3). In contrast, the number of annual deaths from liver cancer increased by 17.8% (95% CI: 17.6–18.0) and the crude death rate increased by 10.2% (95% CI: 10.0–10.4) from 20.5 to 22.6, although the age-standardized death rate decreased by 26.9% (95% CI: 26.6–27.2). The annual number of patients receiving oral antiviral agents against HBV increased from 1,716 to 187,226 during the study period [21] (Table 2).

The age-standardized mortality rate of liver cancer and incidence rate greatly decreased from 24.7 and 33.8, respectively, in 1999, to 16.4 and 19.9, respectively, in 2014. The dissociation between crude rates and age-standardized rates for liver cancer mortality and incidence may be explained by the rapidly aging population in Korea. The crude rates and absolute number of liver cancer mortality and incidence rates continue to increase. These data suggest that liver cancer is currently the most important cancer to overcome in Korea [30].

Previous studies reported a dissociation between trends in total death (increased) and age-standardized death rate (decreased) in the global burden of the disease [31]. These findings were attributed to changes in population growth and shifts in global age structures. In addition, the competing nature between liver disease mortality and liver cancer mortality should be carefully considered [21]. For example, in terms of the absolute death number, the wide use of antiviral drugs for hepatitis B and C may cause a rapid decline in liver disease mortality. Expanding the number of the at-risk population, however, may inadvertently lead to an increase in the absolute liver cancer incidence and mortality.

To observe prevention of HCC, a randomized controlled trial involving patients given ETV, TDF, or TAF and untreated patients would not be realistic. To reach a consensus, a comparison should be conducted between the incidence of HCC in ETV- or TDF-treated and untreated HBV patients (control group) using the propensity scored matching method adjusted for a number of HCC risk factors, as described previously [26, 27] (Table 2).

The immune-tolerant phase, representing the early phase of the CHB, is not well understood. The concept of true immune-tolerance has been underestimated from the viewpoint of immunology and major international guidelines from AASLD, EASL, and APASL have not yet reached a consensus on the definition of the immune-tolerant phase [32]. While positive HBeAg, high serum HBV DNA levels, and normal serum ALT levels are the 3 key features of this phase, the APASL guidelines also take age into consideration [8] (Table 1). No consensus has been reached, however, regarding the lower cutoff level of HBV DNA for defining the immune-tolerant phase, which varies between 6 log10 IU/mL and 2 × 7 log10 IU/mL in clinical practice guidelines [4, 7, 8, 33]. A new nomenclature, Phase 1 or HBeAg-positive chronic HBV infection, is given by the latest version of the EASL guidelines published in April 2017 [4]. Although current major international guidelines advise against starting antiviral treatment for immune-tolerant CHB patients [4, 7, 8] (Table 1), some new data suggest that treating such patients may reduce the risk of liver fibrosis and the progression to HCC.

Current practice guidelines recommend delaying therapy until patients show significantly increased ALT levels or evidence of inflammation and/or fibrosis on biopsy [4, 7, 8, 33] (Table 1). These recommendations are based on the notion that disease progression to hepatic fibrosis and cirrhosis begins with an immune-active phase.

In a natural cohort study of CHB patients (REVEAL-HBV study), the HCC risk was highest at HBV titers >106 copies/mL (∼5 log10 IU/mL) regardless of serum ALT levels or HBeAg [34]. In previous studies, patients with HBV DNA levels at 106–107 copies/mL had a significantly higher risk of HCC compared with those having persistent HBV DNA levels >107 copies/mL or <106 copies/mL [34].

A cohort study in Korea was conducted with 6,949 noncirrhotic, treatment-naïve CHB patients (mean age 45 years) having ALT levels <2 times the upper limit of normal for 1 year. During 8.0 years of median follow-up, 363 patients (5.2%) developed HCC. By multivariate Cox regression analysis, the HCC risk was highest with a baseline HBV DNA level of 6–7 log10 IU/mL (HR 4.98, p < 0.001) and lowest with a baseline HBV DNA level of >8 log10 IU/mL (HR 0.90, p = 0.71) and ≤4 log10 IU/mL (HR 1.00, reference), independent of other predictive factors. The HCC risk was highest with a moderate serum HBV DNA level of 6–7 log10 IU/mL in CHB patients without significant ALT elevation [1].

Untreated patients in the immune-tolerant phase have a significantly higher risk of HCC than immune-active phase patients treated with NAs [9]. The presence of significant hepatic necroinflammation/fibrosis is a significant risk factor for HCC and liver disease progression. Few patients, however, undergo repeat liver biopsy because of its invasive nature. The use of noninvasive tests for hepatic fibrosis is also limited because of their inaccuracy in identifying a significant fibrosis (i.e., F2 fibrosis). Those with a positive family history of HCC and African ethnicity may harbor a greater risk of HCC [17-19].

Untreated HBeAg-negative CHB patients with a high viral load but no significant increase in ALT levels display a higher risk of clinical events than treated patients in an active phase with elevated ALT [35]. The relation between the occurrence of HCC and high HBV DNA levels without ALT elevation is viewed as follows.

Selection and expansion of clonal hepatocytes are major risk factors for HCC and are observed without increased ALT levels or hepatic fibrosis [36-39]. Therefore, reduction of HBV DNA levels to <8 log10 IU/mL, despite its persistence at >4 log10 IU/mL in HBeAg-positive CHB patients, suggests clonal hepatocyte expansion and an increased risk of HCC, even with persistently normal ALT levels. HBV DNA integration into human host chromosomes may further increase chromosomal instability [36].

Progressive integration of the HBV genome into human host chromosomes may increase serum HBV DNA levels to >4 log10 IU/mL in HBeAg-negative patients [40, 41]. A recent study demonstrated that increasing levels of viremia above 20,000 IU/mL indicate a higher frequency of HBV-host genome integration in HBeAg-negative patients currently not indicated for treatment [40]. Random integration of the viral genome into host chromosomes may result in the loss of tumor suppressor gene functions, and/or the activation of tumor-promoting genes that are specifically involved in hepatocarcinogenesis [38, 40].

A recent study demonstrated that inhibition of HBV replication by TDF reduces the number of transcriptionally active distinct HBV-host DNA integrations in patients with HBV viremia above 2,000 IU/mL and minimally elevated ALT levels [42]. Thus, the findings mentioned above [35] may explain the high HCC risk in individuals with increased HBV DNA levels (>4 log10 IU/mL) among HBeAg-negative CHB patients. It is well known that HBV-associated hepatocarcinogenesis occurs without signs of significant hepatic inflammation and/or fibrosis [35].

Several studies have consistently shown that the application of current guideline recommendations may be too late to considerably prevent HCC, although the progression of fibrosis may be blocked [9, 21, 35]. If the goal of antiviral treatment is more the prevention of HCC than the prevention of hepatic inflammation and/or fibrosis progression, the recommendations may have to be considered with caution [43].

Early treatment intervention should therefore be considered to prevent HCC before ALT levels increase in patients with moderate viral loads of between 4 and 8 log10 IU/mL, especially those older than 40 years of age. Accumulating data on the long-term efficacy and safety of anti-HBV drugs such as ETV, TDF, and TAF offer a potent high genetic barrier to resistance, and decreasing their cost may facilitate initiation of early treatment [44-46]. With these considerations in mind, recent findings may help provide appropriate treatment options to obviate HCC in CHB patients [1].

Given the poor prognosis of patients with HCC, these findings may have considerable clinical implications toward preventing cancer in patients with CHB. Current treatment guidelines for CHB should be interpreted with caution given that HBV-associated hepatocarcinogenesis could be underway in patients who are not eligible for antiviral therapies by current guidelines. Therefore, efforts to reconcile treatment guidelines with recent clinical evidence should be made to further reduce the development of HCC [47].

Additional studies are needed to refine HCC risk prediction models by incorporating a broad range of HBV DNA levels. Randomized controlled trials based on those accurate models may be warranted to determine whether antiviral treatment reduces the risk of HCC in noncirrhotic CHB patients with moderate levels of HBV DNA and no significant ALT increase [1].

ETV, TDF, and TAF in the AASLD and EASL guidelines, and ETV and TDF in the APASL guidelines are equally recommended as first-line NAs for CHB in clinical settings because of their similarly high antiviral efficacy and low rate of resistance [4, 7, 8] (Table 1). Regarding the reduction of HCC with NAs such as ETV and TDF, however, the results are controversial and inconsistent in a number of studies demonstrating more favorable outcomes with TDF than with ETV treatment. A study comparing ETV and TAF showed no difference between the 2 groups in reducing the HCC risk [48]. Another recent real-world data study indicates that TAF has comparable efficacies to TDF in terms of the risk of HCC [49].

In Korea, one of the most HB-endemic nations, a nationwide cohort study, validated by a hospital cohort for the first time demonstrated that CHB patients treated with TDF were at significantly lower risk of developing HCC than those treated with ETV [24]. In the national cohort, the annual incidence rate of HCC was significantly lower in the TDF group (n = 12,692, 0.89 per 100 PY) than in the ETV group (n = 11,464, 1.19 per 100 PY). By multivariate-adjusted analysis, TDF therapy was associated with a significantly lower risk of HCC (HR 0.68, 95% CI: 0.59–0.77). Compared with the ETV group (n = 1,560), the TDF group also showed a significantly lower risk of HCC in the 10,923-pair propensity score-matched national cohort (HR 0.68, 95% CI: 0.60–0.78) and 869-pair propensity score-matched hospital cohort (HR 0.68, 95% CI: 0.46–0.99, Table 3) [24].

Table 3.

Comparison of ETV, TDF, and TAF on reduction of HCC

Comparison of ETV, TDF, and TAF on reduction of HCC
Comparison of ETV, TDF, and TAF on reduction of HCC

Furthermore, HCC recurrence was compared between patients treated with TDF or ETV after surgical resection of HBV-related HCC. A cohort study conducted between 2010 and 2018 included 1,695 consecutive patients treated with ETV (n = 813) or TDF (n = 882) after curative-intent hepatectomy for HBV-related HCC of Barcelona Clinic Liver Cancer stage 0 or A. Posthepatectomy, HCC recurrence and overall survival were compared between the ETV- and TDF-treated groups by propensity score matching and multivariate-adjusted Cox regression analyses (Tables 4, 5).

Table 4.

Experts’ opinions regarding prevention of HCC with NAs and approaches to solve these controversies

Experts’ opinions regarding prevention of HCC with NAs and approaches to solve these controversies
Experts’ opinions regarding prevention of HCC with NAs and approaches to solve these controversies
Table 5.

Experts’ opinions regarding comparison of ETV, TDF, and TAF on reduction of HCC and approaches to solve these controversies

Experts’ opinions regarding comparison of ETV, TDF, and TAF on reduction of HCC and approaches to solve these controversies
Experts’ opinions regarding comparison of ETV, TDF, and TAF on reduction of HCC and approaches to solve these controversies

During the median follow-up of 37.6 months with continued ETV or TDF therapy, HCC recurred in 561 (33.1%) patients. By multivariate-adjusted analysis, the TDF group demonstrated significantly lower rates of HCC recurrence (HR 0.82; 95% CI: 0.68–0.98; p = 0.03) and death or transplantation (HR 0.62; 95% CI: 0.44–0.88; p = 0.01; Table 3) [10].

The mechanisms of TDF and ETV, with the former imparting a significantly lower risk of HCC than the latter, might be explained, in part, by the better virologic response profiles of the TDF group, as shown in the hospital cohort, and in other studies [50-52]. Nevertheless, considering that a virologic response is not an independent risk factor for HCC, the difference in the HCC risk after TDF or ETV treatment cannot be fully explained by their antiviral potency. A recent study demonstrated that higher serum IFN-λ3 levels are induced in patients treated with the nucleotide analogs adefovir dipivoxil and TDF, but not in those treated with the nucleoside analogs LAM and ETV [53]. IFN-λ exhibits potent antitumor activity in murine models of cancer, including hepatoma [54, 55]; this antitumor activity is assumed to contribute to the difference in the HCC risk. Moreover, ETV is carcinogenic in mice and rats when administered at doses higher than those used in humans [24]. Also, ETV is known to potentially incorporate into the human genome and to contribute to a putative mechanism of carcinogenicity, especially when the embedded genome has higher error rates during subsequent rounds of replication [56-58]. These data raise concerns about the carcinogenic potential of ETV, even at clinical doses during long-term treatment, especially in patients with cirrhosis and increased chromosomal instability of hepatocytes [59, 60].

Several reports from Korea, however, have questioned the conclusions reached in other studies. A total of 7,015 consecutive patients diagnosed with CHB were treated with TDF or ETV between February 2007 and January 2018 at the liver unit of the Catholic University of Korea and screened for study eligibility: finally, 3,022 patients (ETV: 1,583, TDF: 1,439) were analyzed. No difference in the incidence rate of HCC between TDF and ETV therapy was detected in the entire cohort (HR 1.030, 95% CI: 0.703–1.509, p = 0.880; Table 3) or in subgroups with chronic hepatitis and cirrhosis [15].

In a study of 404 CHB patients (ETV n = 180, TDF n = 224), TDF was associated with a lower incidence of HCC (HR 0.31, 95% CI: 0.12–0.79; p = 0.014), but no statistical significance was detected after adjusting for sustained virologic suppression through propensity score matching (HR 0.36, 95% CI: 0.12–1.14; p = 0.08; Table 3) [61]. Regarding the mechanism underlying the equivalent effects of ETV and TDF on the reduction of HCC, a Korean study observed that the hypothesis of the induction of IFN-λ3 production by TDF and the carcinogenic potential of ETV is problematic [48].

First, the level of serum IFN-λ3 imparts higher anticarcinogenic and antiviral effects to patients treated with TDF than to those treated with ETV, but conflicting data are also reported [17, 62-65]. Moreover, because IFN-λ assays are not standardized, the causality of the relation between higher IFN-λ3 levels and a lower incidence of HCC requires further investigation.

Second, in mice, ETV at 4 mg/kg increases the incidence of lung adenoma and carcinoma, HCC, and vascular tumors, and at 1.4–2.6 mg/kg increases the incidence of HCC, brain microglial tumors, and skin fibroma [66]. These doses, however, are at least 100-fold higher than those used in humans. In contrast, 2 recent large-scale real-life studies demonstrated that long-term ETV therapy does not increase the risk of cancer [67, 68]. Moreover, in a long-term follow-up study [69], the incidence of HCC did not differ statistically during or after the first 5 years of ETV treatment (2.29% vs. 1.66%, p = 0.22); should long-term ETV administration induce a significant procarcinogenic effect in humans, the HCC incidence would progress rapidly over time.

A recent Korean study comparing the impact of ETV and TAF on the reduction of HCC [48] demonstrated no statistical difference in the annual incidence of HCC in ETV (n = 1,525) and TAF (n = 286) patients (1.67 vs. 1.19 per 100 PY, respectively) with HR 0.681, 95% CI: 0.351–1.320, p = 0.255, as determined by propensity score matching methods, suggesting that ETV- and TAF-treated CHB patients face a similar risk of developing HCC [48]. Studies from China, Taiwan, and Hong Kong as well as from Korea report conflicting results regarding the efficacy of ETV and TDF for obviating HCC [11, 14-16, 24].

In a large nationwide cohort study in Hong Kong, 29,350 treatment-naive CHB patients were started on ETV (n = 28,041) and TDF (n = 1,309) as first-line therapy. After propensity score weighting and 1:5 matching, TDF was associated with a lower risk of HCC than ETV (HR 0.36, 95% CI: 0.16–0.80, p = 0.013; Table 3) [11].

In a meta-analysis from Hong Kong, 85,008 CHB patients received ETV (n = 56,346) and TDF (n = 28,662); TDF was associated with a lower HCC risk than ETV, particularly in cirrhotic patients (HR 0.73, 95% CI: 0.62–0.85, p < 0.001; Table 3) [70]. Taiwan and Asia-Pacific study showed no association between TDF (n = 700) and ETV (n = 4,837) regimens with HCC risk in a multivariable-adjusted analysis (HR 0.89, 95% CI: 0.41–1.92, p = 0.77; Table 3) [14].

Another Taiwan and Asia-Pacific study reported that the risk of HCC with TDF (16,266) and ETV (19,702) treatment was similar (primary outcome, TDF: 3.39%/5Y, ETV: 3.44%/5Y; adjusted HR 0.88, 95% CI: 0.73–1.07; p = 0.20) by analysis of 14 comparative studies with covariate adjustment. No significant difference between TDF and ETV in their association with incident HCC was observed [71].

In a total of 3,698 patients (1,574 under TDF therapy, and 2,124 under ETV therapy) in China, TDF was more efficacious than ETV in mitigating the HCC incidence (rate ratio [RR-HR combined with incidence rate ratios] 0.66, 95% CI: 0.49–0.89, p = 0.008; Table 3), indicating that TDF should be used more widely in treating CHB patients [12].

In contrast to the above conflicting Korean and Asian data, European and American studies have concluded that ETV and TDF provide similar efficacy. A European study in 1935 Caucasians with CHB treated with ETV (n = 772) and TDF (n = 1,163) demonstrated similar HCC risk in the 2 groups (ETV: 1.08% PY, TDF: 1.2% PY, p = 0.321; Table 3) [72].

In the USA, no difference in the risk of HCC was detected between veteran-affairs patients treated with ETV (n = 2,193) and TDF (n = 1,094) before and after propensity score matching (HR 1.00, 95% CI: 0.76–1.32; Table 3) [73]. The controversial results can be partly attributed to the arbitrary nature of significance levels, leading to contradictory conclusions from very similar datasets. The use of observational data, however, which is prone to both within- and between-study heterogeneity of patient characteristics, also lends additional uncertainty. The synchronous introduction of ETV and TDF in East Asia, where the majority of these studies were conducted, further complicates analyses, as does the difference in the follow-up times between ETV and TDF cohorts. Researchers conducting meta-analyses in this area must make many methodologic decisions to mitigate bias but are ultimately limited to the methodologies of the included studies. It is therefore important for researchers, as well as the audience of published meta-analyses, to be aware of the quality of observational studies and meta-analyses in terms of patient characteristics, study design, and statistical methodologies [74].

It is important to note that all the studies comparing the risk of HCC between TDF and ETV therapies have indicated one direction favoring TDF or no direction. No high-quality studies have provided evidence favoring ETV over TDF [13]. Further clinical studies or trials with a larger number of patients and longer follow-up are needed to resolve these controversial issues and to reach a consensus.

Serum levels of HBV DNA are closely associated with the risk of HCC in CHB patients independent of HBeAg and ALT levels. Treatment with NAs, including ETV, TDF, and TAF, may lower the risk of HCC incidence and recurrence in such patients. Three issues have constrained the resolution of CHB treatment and the obviation of subsequent HCC.

1.The AASLD [7], APASL [8], and EASL [4] guidelines for the management of HBV infection recommend antiviral treatment for HBV with IFN and NAs for the prevention of HCC. Among experts in CHB treatment, however, continuing controversy exists regarding antiviral treatment for the optimal prevention of HCC. A growing evidence from large-scale cohort studies suggests that early initiation of antiviral treatment even with persistently normal ALT levels may be necessary to minimize the risk of HCC.

2.The AASLD, EASL, and APASL guidelines make no recommendations for antiviral treatment in patients in the immune-tolerant phase of CHB, especially patients younger than 30 years of age. Nonetheless, the cutoff level of lower serum HBV DNA levels for the definition of the immune-tolerant phase CHB is not consistent across the guidelines. Even if we have the consensus for the definition of immune-tolerant phase CHB, many patients remain in the gray zone with no treatment recommendations.

3.Whether ETV, TDF, and TAF treatments have different effects on the prevention of HCC is not clear yet. To resolve this issue, we suggest a meta-analysis by using individual patient data from the cohort studies or randomized trials with a larger number of subjects and longer follow-up.

The authors thank Ms. Mika Matsui for excellent technical assistance.

Young-Suk Lim is an advisory board member of Bayer Healthcare and Gilead Sciences and receives investigator-initiated research funding from Bayer Healthcare and Gilead Sciences. Masatoshi Kudo reports receiving lecture fees from Eisai, Bayer, MSD, Bristol-Myers Squibb, Lilly, and EA Pharma; receiving grants from Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, AbbVie, and Eisai; and having advisory roles at Eisai, Ono, MSD, Bristol-Myers Squibb, and Roche. The other authors have no conflicts of interest to disclose.

There was no industry involvement in the design, conduct, or analysis of the study. This study was supported by grants from the Patient-Centered Clinical Research Coordinating Center (PACEN; Grant No. HC20C0062) of the National Evidence-based Healthcare Collaborating Agency and the National R&D Program for Cancer Control through the National Cancer Center (Grant No: HA21C0110), funded by the Ministry of Health & Welfare, Republic of Korea. The funding sources had no role in the design of this study, its execution, analyses, interpretation of the data, or decision to submit the results.

Kim S.K., Fujii T., Kim S.R., Nakai A., and Hagiwara S. wrote the manuscript; Lim Y.-S. and Kudo M. approved the final version.

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Moderate levels of serum hepatitis B virus DNA are associated with the highest risk of hepatocellular carcinoma in chronic hepatitis B patients
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Aliment Pharmacol Ther
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2020 Jun
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1169
79
. .
2.
Foreman
KJ
,
Marquez
N
,
Dolgert
A
,
Fukutaki
K
,
Fullman
N
,
McGaughey
M
,
Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories
.
Lancet
.
2018 Nov
;
392
(
10159
):
2052
90
. .
3.
Thomas
DL
.
Global elimination of chronic hepatitis
.
N Engl J Med
.
2019 May
;
380
(
21
):
2041
50
. .
4.
European Association for the Study of the Liver Electronic address easloffice@easlofficeeu
.
EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection
.
J Hepatol
.
2017 Aug
;
67
(
2
):
370
98
. .
5.
Varbobitis
I
,
Papatheodoridis
GV
.
The assessment of hepatocellular carcinoma risk in patients with chronic hepatitis B under antiviral therapy
.
Clin Mol Hepatol
.
2016 Sep
;
22
(
3
):
319
26
. .
6.
Papatheodoridis
GV
,
Idilman
R
,
Dalekos
GN
,
Buti
M
,
Chi
H
,
van Boemmel
F
,
The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B
.
Hepatology
.
2017 Nov
;
66
(
5
):
1444
53
. .
7.
Terrault
NA
,
Lok
ASF
,
McMahon
BJ
,
Chang
KM
,
Hwang
JP
,
Jonas
MM
,
Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance
.
Hepatology
.
2018 Apr
;
67
(
4
):
1560
99
. .
8.
Sarin
SK
,
Kumar
M
,
Lau
GK
,
Abbas
Z
,
Chan
HLY
,
Chen
CJ
,
Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update
.
Hepatol Int
.
2016 Jan
;
10
(
1
):
1
98
. .
9.
Kim
GA
,
Lim
YS
,
Han
SB
,
Choi
JG
,
Shim
JH
,
Kim
KM
,
High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B
.
Gut
.
2018 May
;
67
(
5
):
945
52
. .
10.
Choi
JG
,
Jo
CY
,
Lim
YS
.
Tenofovir versus entecavir on recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection
.
Hepatology
.
2021 Feb
;
73
(
2
):
661
73
. .
11.
Yip
TCF
,
Wong
VWS
,
Chan
HLY
,
Tse
YK
,
Lui
GCY
,
Wong
GLH
.
Tenofovir is associated with lower risk of hepatocellular carcinoma than entecavir in patients with chronic HBV infection in China
.
Gastroenterology
.
2020
;
158
(
1
):
215
25.e6
. .
12.
Zhang
Z
,
Zhou
Y
,
Yang
J
,
Hu
K
,
Huang
Y
.
The effectiveness of TDF versus ETV on incidence of HCC in CHB patients: a meta-analysis
.
BMC Cancer
.
2019 May
;
19
(
1
):
511
. .
13.
Choi
JG
,
Lim
YS
.
Comparison of risk of hepatocellular carcinoma between tenofovir and entecavir: one direction or no direction
.
J Hepatol
.
2019 Oct
;
71
(
4
):
846
7
. .
14.
Hsu
YC
,
Wong
GLH
,
Chen
CH
,
Peng
CY
,
Yeh
ML
,
Cheung
KS
,
Tenofovir versus entecavir for hepatocellular carcinoma prevention in an international consortium of chronic hepatitis B
.
Am J Gastroenterol
.
2020 Feb
;
115
(
2
):
271
80
. .
15.
Lee
SW
,
Kwon
JH
,
Lee
HL
,
Yoo
SH
,
Nam
HC
,
Sung
PS
,
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 Jul
;
69
(
7
):
1301
8
. .
16.
Kim
SU
,
Seo
YS
,
Lee
HA
,
Kim
MN
,
Lee
YR
,
Lee
HW
,
A multicenter study of entecavir vs. tenofovir on prognosis of treatment-naive chronic hepatitis B in South Korea
.
J Hepatol
.
2019 Sep
;
71
(
3
):
456
64
. .
17.
Heimbach
JK
,
Kulik
LM
,
Finn
RS
,
Sirlin
CB
,
Abecassis
MM
,
Roberts
LR
,
AASLD guidelines for the treatment of hepatocellular carcinoma
.
Hepatology
.
2018 Jan
;
67
(
1
):
358
80
. .
18.
Galle
PR
,
Forner
A
,
Llovet
JM
,
Mazzaferro
V
,
Piscaglia
F
,
Raoul
JL
,
EASL clinical practice guidelines: management of hepatocellular carcinoma
.
J Hepatol
.
2018 Jul
;
69
(
1
):
182
236
. .
19.
Omata
M
,
Cheng
AL
,
Kokudo
N
,
Kudo
M
,
Lee
JM
,
Jia
J
,
Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update
.
Hepatol Int
.
2017 Jul
;
11
(
4
):
317
70
. .
20.
Kim
GA
,
Lim
YS
,
An
J
,
Lee
D
,
Shim
JH
,
Kim
KM
,
HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability
.
Gut
.
2014 Aug
;
63
(
8
):
1325
32
. .
21.
Choi
JG
,
Han
S
,
Kim
N
,
Lim
YS
.
Increasing burden of liver cancer despite extensive use of antiviral agents in a hepatitis B virus-endemic population
.
Hepatology
.
2017 Nov
;
66
(
5
):
1454
63
. .
22.
Lim
YS
,
Han
SB
,
Heo
NY
,
Shim
JH
,
Lee
HC
,
Suh
DJ
.
Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine
.
Gastroenterology
.
2014 Jul
;
147
(
1
):
152
61
. .
23.
Kim
GA
,
Han
S
,
Kim
HD
,
An
J
,
Lim
YS
.
Higher risk of hepatocellular carcinoma in chronic hepatitis B vs chronic hepatitis C after achievement of virologic response
.
J Viral Hepat
.
2017 Nov
;
24
(
11
):
990
7
. .
24.
Choi
JG
,
Kim
HJ
,
Lee
JY
,
Cho
SH
,
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 Jan
;
5
(
1
):
30
6
. .
25.
Liaw
YF
,
Sung
JJY
,
Chow
WC
,
Farrell
G
,
Lee
CZ
,
Yuen
H
,
Lamivudine for patients with chronic hepatitis B and advanced liver disease
.
N Engl J Med
.
2004 Oct
;
351
(
15
):
1521
31
. .
26.
Wong
GLH
,
Chan
HLY
,
Mak
CWH
,
Lee
SKY
,
Ip
ZMY
,
Lam
ATH
,
Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis
.
Hepatology
.
2013 Nov
;
58
(
5
):
1537
47
. .
27.
Hosaka
T
,
Suzuki
F
,
Kobayashi
M
,
Seko
Y
,
Kawamura
Y
,
Sezaki
H
,
Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection
.
Hepatology
.
2013 Jul
;
58
(
1
):
98
107
. .
28.
Wu
CY
,
Lin
JT
,
Ho
HJ
,
Su
CW
,
Lee
TY
,
Wang
SY
,
Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study
.
Gastroenterology
.
2014 Jul
;
147
(
1
):
143
51.e5
. .
29.
Su
TH
,
Hu
TH
,
Chen
CY
,
Huang
YH
,
Chuang
WL
,
Lin
CC
,
Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients
.
Liver Int
.
2016 Dec
;
36
(
12
):
1755
64
. .
30.
Korean Liver Cancer Association
.
2018 Korean Liver Cancer Association: National Cancer Center Korea practice guidelines for the management of hepatocellular carcinoma
.
Gut Liver
.
2019 May
;
13
(
3
):
227
99
. .
31.
GBD 2015 Mortality and Causes of Death Collaborators
.
Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease study 2015
.
Lancet
.
2016
;
388
(
10053
):
1459
544
. .
32.
Wong
GLH
.
Management of chronic hepatitis B patients in immunetolerant phase: what latest guidelines recommend
.
Clin Mol Hepatol
.
2018 Jun
;
24
(
2
):
108
13
. .
33.
Korean Association for the Study of the Liver KASL
.
KASL clinical practice guidelines for management of chronic hepatitis B
.
Clin Mol Hepatol
.
2019 Jun
;
25
(
2
):
93
159
. .
34.
Chen
CJ
,
Yang
HI
,
Su
J
,
Jen
CL
,
You
SL
,
Lu
SN
,
Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level
.
JAMA
.
2006 Jan
;
295
(
1
):
65
73
. .
35.
Choi
GH
,
Kim
GA
,
Choi
JG
,
Han
SB
,
Lim
YS
.
High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation
.
Aliment Pharmacol Ther
.
2019 Jul
;
50
(
2
):
215
26
. .
36.
Mason
WS
,
Gill
US
,
Litwin
S
,
Zhou
Y
,
Peri
S
,
Pop
O
,
HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant
.
Gastroenterology
.
2016 Nov
;
151
(
5
):
986
98.e4
. .
37.
Mason
WS
,
Liu
C
,
Aldrich
CE
,
Litwin
S
,
Yeh
MM
.
Clonal expansion of normal-appearing human hepatocytes during chronic hepatitis B virus infection
.
J Virol
.
2010 Aug
;
84
(
16
):
8308
15
. .
38.
Chemin
I
,
Zoulim
F
.
Hepatitis B virus induced hepatocellular carcinoma
.
Cancer Lett
.
2009 Dec
;
286
(
1
):
52
9
. .
39.
Marongiu
F
,
Doratiotto
S
,
Montisci
S
,
Pani
P
,
Laconi
E
.
Liver repopulation and carcinogenesis: two sides of the same coin?
Am J Pathol
.
2008 Apr
;
172
(
4
):
857
64
. .
40.
Svicher
V
,
Salpini
R
,
Battisti
A
,
Colagrossi
L
,
Piermatteo
L
,
Surdo
M
,
GS-17-the integration of Hepatitis B virus into human genome is a common event in the setting of HBeAg negative disease: implications for the treatment and management of CHB
.
J Hepatol
.
2019
;
70
(
1
):
e83
4
. .
41.
Wooddell
CI
,
Yuen
MF
,
Chan
HLY
,
Gish
RG
,
Locarnini
SA
,
Chavez
D
,
RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg
.
Sci Transl Med
.
2017 Sep
;
9
(
409
):
eaan0241
. .
42.
Hsu
YC
,
Suri
V
,
Nguyen
MH
,
Huang
YT
,
Chen
CY
,
Chang
IW
,
Inhibition of viral replication reduces transcriptionally active distinct hepatitis B virus integrations with implications on host gene dysregulation
.
Gastroenterology
.
2022 Apr
;
162
(
4
):
1160
70.e1
. .
43.
Zoulim
F
,
Mason
WS
.
Reasons to consider earlier treatment of chronic HBV infections
.
Gut
.
2012 Mar
;
61
(
3
):
333
6
. .
44.
Buti
M
,
Gane
E
,
Seto
WK
,
Chan
HLY
,
Chuang
WL
,
Stepanova
T
,
Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial
.
Lancet Gastroenterol Hepatol
.
2016 Nov
;
1
(
3
):
196
206
. .
45.
Chan
HLY
,
Fung
S
,
Seto
WK
,
Chuang
WL
,
Chen
CY
,
Kim
HJ
,
Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial
.
Lancet Gastroenterol Hepatol
.
2016 Nov
;
1
(
3
):
185
95
. .
46.
Agarwal
K
,
Brunetto
M
,
Seto
WK
,
Lim
YS
,
Fung
S
,
Marcellin
P
,
96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection
.
J Hepatol
.
2018 Apr
;
68
(
4
):
672
81
. .
47.
Choi
JG
,
Lim
YS
.
Secondary prevention of hepatitis B virus-related hepatocellular carcinoma with current antiviral therapies
.
Kaohsiung J Med Sci
.
2021
;
37
(
4
):
262
7
. .
48.
Lee
HW
,
Cho
YY
,
Lee
H
,
Lee
JS
,
Kim
SU
,
Park
JY
,
Impact of tenofovir alafenamide vs. entecavir on hepatocellular carcinoma risk in patients with chronic hepatitis B
.
Hepatol Int
.
2021 Oct
;
15
(
5
):
1083
92
. .
49.
Lim
JH
,
Choi
WM
,
Shim
JH
,
Lee
D
,
Kim
KM
,
Lim
YS
,
Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in treatment-naïve chronic hepatitis B
.
Liver Int
.
2022 Mar
;
42
(
7
):
1517
27
. .
50.
Zuo
SR
,
Zuo
XC
,
Wang
CJ
,
Ma
YT
,
Zhang
HY
,
Li
ZJ
,
A meta-analysis comparing the efficacy of entecavir and tenofovir for the treatment of chronic hepatitis B infection
.
J Clin Pharmacol
.
2015 Mar
;
55
(
3
):
288
97
. .
51.
Batirel
A
,
Guclu
E
,
Arslan
F
,
Kocak
F
,
Karabay
O
,
Ozer
S
,
Comparable efficacy of tenofovir versus entecavir and predictors of response in treatment-naïve patients with chronic hepatitis B: a multicenter real-life study
.
Int J Infect Dis
.
2014 Nov
;
28
:
153
9
. .
52.
Woo
G
,
Tomlinson
G
,
Nishikawa
Y
,
Kowgier
M
,
Sherman
M
,
Wong
DKH
,
Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses
.
Gastroenterology
.
2010 Oct
;
139
(
4
):
1218
29
. .
53.
Murata
K
,
Asano
M
,
Matsumoto
A
,
Sugiyama
M
,
Nishida
N
,
Tanaka
E
,
Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection
.
Gut
.
2018 Feb
;
67
(
2
):
362
71
. .
54.
Abushahba
W
,
Balan
M
,
Castaneda
I
,
Yuan
Y
,
Reuhl
K
,
Raveche
E
,
Antitumor activity of type I and type III interferons in BNL hepatoma model
.
Cancer Immunol Immunother
.
2010 Jul
;
59
(
7
):
1059
71
. .
55.
Sato
A
,
Ohtsuki
M
,
Hata
M
,
Kobayashi
E
,
Murakami
T
.
Antitumor activity of IFN-lambda in murine tumor models
.
J Immunol
.
2006 Jun
;
176
(
12
):
7686
94
. .
56.
Brown
JA
,
Pack
LR
,
Fowler
JD
,
Suo
Z
.
Presteady state kinetic investigation of the incorporation of anti-hepatitis B nucleotide analogues catalyzed by noncanonical human DNA polymerases
.
Chem Res Toxicol
.
2012 Jan
;
25
(
1
):
225
33
. .
57.
Jiang
L
,
Wu
X
,
He
F
,
Liu
Y
,
Hu
X
,
Takeda
S
,
Genetic evidence for genotoxic effect of entecavir, an anti-hepatitis B virus nucleotide analog
.
PLoS One
.
2016 Jan
;
11
(
1
):
e0147440
. .
58.
Brambilla
G
,
Mattioli
F
,
Robbiano
L
,
Martelli
A
.
Studies on genotoxicity and carcinogenicity of antibacterial, antiviral, antimalarial and antifungal drugs
.
Mutagenesis
.
2012 Jul
;
27
(
4
):
387
413
. .
59.
Wilkens
L
,
Flemming
P
,
Gebel
M
,
Bleck
J
,
Terkamp
C
,
Wingen
L
,
Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma
.
Proc Natl Acad Sci USA
.
2004 Feb
;
101
(
5
):
1309
14
. .
60.
Wiemann
SU
,
Satyanarayana
A
,
Tsahuridu
M
,
Tillmann
HL
,
Zender
L
,
Klempnauer
J
,
Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis
.
FASEB J
.
2002 Jul
;
16
(
9
):
935
42
. .
61.
Ha
YJ
,
Chon
YE
,
Kim
MN
,
Lee
JH
,
Hwang
SG
.
Hepatocellular carcinoma and death and transplantation in chronic hepatitis B treated with entecavir or tenofovir disoproxil fumarate
.
Sci Rep
.
2020 Aug
;
10
(
1
):
13537
. .
62.
Sinn
DH
,
Lee
J
,
Goo
J
,
Kim
K
,
Gwak
GY
,
Paik
YH
,
Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load
.
Hepatology
.
2015 Sep
;
62
(
3
):
694
701
. .
63.
Cho
YY
,
Lee
JH
,
Chang
Y
,
Nam
JY
,
Cho
H
,
Lee
DH
,
Comparison of overall survival between antiviral-induced viral suppression and inactive phase chronic hepatitis B patients
.
J Viral Hepat
.
2018 Oct
;
25
(
10
):
1161
71
. .
64.
Lee
SB
,
Jeong
J
,
Park
JH
,
Jung
SW
,
Jeong
ID
,
Bang
SJ
,
Low-level viremia and cirrhotic complications in patients with chronic hepatitis B according to adherence to entecavir
.
Clin Mol Hepatol
.
2020 Jul
;
26
(
3
):
364
75
. .
65.
Hsu
YC
,
Yip
TCF
,
Ho
HJ
,
Wong
VWS
,
Huang
YT
,
El-Serag
HB
,
Development of a scoring system to predict hepatocellular carcinoma in Asians on antivirals for chronic hepatitis B
.
J Hepatol
.
2018 Aug
;
69
(
2
):
278
85
. .
66.
Laccetti
M
,
Manes
G
,
Uomo
G
,
Lioniello
M
,
Rabitti
PG
,
Balzano
A
.
Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double blind randomized placebo controlled study
.
Dig Liver Dis
.
2000 May
;
32
(
4
):
335
8
. .
67.
Chao
X
,
Qian
H
,
Wang
S
,
Fulte
S
,
Ding
WX
.
Autophagy and liver cancer
.
Clin Mol Hepatol
.
2020 Oct
;
26
(
4
):
606
17
. .
68.
Yoon
SM
,
Kim
SY
,
Lim
YS
,
Kim
KM
,
Shim
JH
,
Lee
D
,
Stereotactic body radiation therapy for small (≤5 cm) hepatocellular carcinoma not amenable to curative treatment: results of a single-arm, phase II clinical trial
.
Clin Mol Hepatol
.
2020 Oct
;
26
(
4
):
506
15
. .
69.
Kim
BG
,
Park
NH
,
Lee
SB
,
Jeon
S
,
Park
JH
,
Jung
SW
,
The risk of hepatocellular carcinoma within and beyond the first 5 years of entecavir in Korean patients with chronic hepatitis B
.
Liver Int
.
2018 Dec
;
38
(
12
):
2269
76
. .
70.
Cheung
KS
,
Mak
LY
,
Liu
SH
,
Cheng
HM
,
Seto
WK
,
Yuen
MF
,
Entecavir vs tenofovir in hepatocellular carcinoma prevention in chronic hepatitis B infection: a systematic review and meta-analysis
.
Clin Transl Gastroenterol
.
2020 Oct
;
11
(
10
):
e00236
. .
71.
Tseng
CH
,
Hsu
YC
,
Chen
TH
,
Ji
F
,
Chen
IS
,
Tsai
YN
,
Hepatocellular carcinoma incidence with tenofovir versus entecavir in chronic hepatitis B: a systematic review and meta-analysis
.
Lancet Gastroenterol Hepatol
.
2020 Dec
;
5
(
12
):
1039
52
. .
72.
Papatheodoridis
GV
,
Dalekos
GN
,
Idilman
R
,
Sypsa
V
,
Van Boemmel
F
,
Buti
M
,
Similar risk of hepatocellular carcinoma during long-term entecavir or tenofovir therapy in Caucasian patients with chronic hepatitis B
.
J Hepatol
.
2020 Nov
;
73
(
5
):
1037
45
. .
73.
Su
F
,
Berry
K
,
Ioannou
GN
.
No difference in hepatocellular carcinoma risk between chronic hepatitis B patients treated with entecavir versus tenofovir
.
Gut
.
2021
;
70
(
2
):
370
8
. .
74.
Choi
WM
,
Yip
TCF
,
Lim
YS
,
Wong
GLH
,
Kim
WR
.
Methodological challenges of performing meta-analyses to compare the risk of hepatocellular carcinoma between chronic hepatitis B treatments
.
J Hepatol
.
2022 Jan
;
76
(
1
):
186
94
. .
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