Hot Keywords
non-alcoholic fatty liver disease epidemiology nonalcoholic steatohepatitis transplantation cholangiocarcinoma direct-acting antiviral immunotherapy hepatitis B hepatitis C liver resection imaging cancer stem cell diagnosis gene cirrhosis biomarker recurrence

Hepatoma Res 2017;3:302-308.10.20517/2394-5079.2016.44© The Author(s) 2017.
Open AccessReview

The impact of nucleos(t)ide analog therapy in hepatitis B on the incidence of hepatocellular carcinoma: an update including recent literature findings

1Department of Gastroenterology and Hepatology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.

2David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.

3Division of Hepatology, Department of Medicine, University of Miami Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

4Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.

Correspondence Address: Dr. Walid S. Ayoub, Department of Gastroenterology and Hepatology, Cedars Sinai Medical Center, 8900 Beverly Blvd, Suite 250, Los Angeles, CA 90048, USA. E-mail:

    Views:2474 | Downloads:624 | Citations:0 | Comments:0 | :1

    This is an open access article licensed under the terms of Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, as long as the original author is credited and the new creations are licensed under the identical terms.


    Worldwide, hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality. In men, it is the fifth most common cancer and seventh most common in women; HCC is the second highest cause of cancer-related death worldwide. It is less prevalent in the USA and Northern Europe and more prevalent in Eastern and South-Eastern Asia. Over 700,000 cases are diagnosed each year - half of which occur in China - and result in roughly the same number of deaths per year. HCC significantly impairs quality of life and is associated with great costs to society. It is estimated that half of the deaths from HCC are associated with hepatitis B virus (HBV). Fortunately, HBV vaccination and antiviral therapy have shown excellent efficacy in decreasing the incidence of HCC. We will discuss the relationship of HBV to HCC, address available treatments for HBV and the impact of treatment on the development of HCC.


    Hepatitis B virus (HBV) is a DNA virus that incorporates into the host genome and thereby increases the risk of developing hepatocellular carcinoma (HCC). This risk of HCC is increased even in patients with HBV without cirrhosis; the risk of developing HCC is up to 100 fold higher in persons infected with hepatitis B compared to uninfected persons[1]. An effective strategy shown to decrease the incidence of HCC is vaccination against HBV. A recent analysis of two Taiwanese HCC registries of 1,509 patients diagnosed with HCC from 1983-2011 demonstrated an incidence per 105 person-years of 0.92 in the unvaccinated cohort and 0.23 in the vaccinated cohort[2]. Another appealing strategy to decrease the incidence of HCC in patients with chronic hepatitis B is inhibition of viral replication. In the seminal study by Liaw et al.[3], the chemopreventive effect of nucleos(t)ides was first suggested as the suppression of HBV replication led to decreased rates of cirrhosis, liver failure, and the development of HCC.

    The relationship between HBV and HCC

    Chronic hepatitis B (CHB) stimulates the immune system to release cytokines and reactive oxygen species, which cause damage to genes, results in cell death and initiates a cascade of fibrosis. As a result, the hepatocyte cell cycle is accelerated and leads to accumulation of genetic alterations, which leads to malignant transformation of hepatocytes[4]. In addition, HBV integrates into the host DNA where it modifies the expression of certain oncogenes. Certain mutations have been implicated in contributing to a higher incidence of HCC. These include the HBV protein known as HBx, infection with HBV genotype C, the hepatitis B genome mutations pre-S deletions and core promoter mutations (V1735, T1762 and A1764)[4,5]. Another risk factor is the level of the hepatitis B surface antigen (HBsAg) titer. Levels of HBsAg that are greater than 1,000 IU/mL may independently predict increased risk for developing HCC in Asians in HBeAg negative patients with low HBV viral load[6]. One retrospective study examined the cumulative probability of HCC development over time despite long-term nucleos(t)ide analog (NA) therapy. The study included treatment-naive CHB patients (n = 524) who received treatment with NAs between January 2003 and December 2007 for longer than 48 weeks. The study revealed a cumulative probability of developing HCC at 1, 2, 3, 4 and 5 years of 0.2%, 1.8%, 3.6%, 5.8%, and 9.3% respectively. In multivariate analysis, age greater than 50 years [hazard ratio (HR) 1.05], family history of HCC (HR 5.48), and the presence of cirrhosis (HR 17.16) were significant predictors of HCC development. Importantly, maintaining a virologic response or HBV DNA < 20 IU/mL for longer than 12 months reduced the risk of HCC development (HR 0.09)[7]. These studies suggest that persistent HBV viral replication and subsequent liver injury are major risk factors for developing HCC.

    The incidence of HBV-related HCC varies between the western world and Asia; the 5-year cumulative incidences of HCC in Asia among inactive carriers and those with compensated cirrhosis are 1% and 17%, respectively. In Europe and the United States, those incidences are 0.1% and 10%[8]. A recent meta-analysis evaluated 66 studies with a total of 347,859 patients using multivariate regression analysis, and after adjusting for age, there were no significant differences in HCC incidence between Western and European studies. The analysis showed that age, symptomatic carrier status, chronic hepatitis, or compensated cirrhosis were the greatest risk factors for development of HCC when compared to inactive carriers[9].

    Goals of HBV therapy

    There are 7 drugs currently approved for the treatment of CHB and they can be divided into 2 groups. The immune-modulators include pegylated interferon alfa-2a and interferon alfa-2b. The NA are oral medications, which include lamivudine, telbivudine, adefovir, tenofovir and entecavir. The oral agents have a better side effect profile and thus, most patients are treated with oral therapy. Goals of treating CHB in the short term include suppressing replication with induction of hepatitis B e-antigen (HBeAg) seroconversion in patients with HBeAg-positive CHB and normalization of alanine aminotransferase. In the long term, the goal is to achieve seroconversion of HBsAg to hepatitis B surface antibody. However, HBsAg seroconversion is not common with currently available therapies. It is seen in 1% and 1.5% of patients after 52 weeks of lamivudine or telbivudine therapy respectively. Furthermore, 5 years of adefovir therapy results in HBsAg loss in only 3% of patients. The rates of HBsAg seroconversion are slightly better with entecavir and tenonfovir. Ninety-six weeks of entecavir results in 5% seroconversion rate and 4 years of tenofovir yields a 10% seroconversion rate. The best HBsAg seroconversion rate (15%) is seen after 72 weeks of treatment with pegylated interferon alfa-2a and lamivudine[10-12]. Although seroconversion of HBsAg doesn’t occur frequently, multiple studies show that treatment favorably impacts fibrosis, survival and reduces HCC development in patients who are treated for CHB.

    The first nucleoside approved for the treatment of HBV was lamivudine. However, development of resistance with prolonged treatment has limited its use. After 5 years of therapy, resistance is reported to be as high as 75%[13]. Telbivudine and adefovir have a moderate genetic barrier to resistance and are considered to be are second line therapies. Currently, entecavir and tenofovir are first line agents for treating CHB because they have such a high barrier to resistance. Many studies with nucleos(t)ide therapy have confirmed a decrease in the rate of HCC in treated patients, regardless of the strength of the proposed treatment’s barrier to resistance.

    Treatment of HBV and HCC

    Antiviral therapy with NAs and interferon can improve liver fibrosis and suppress HBV viral replication, which leads to decreased HCC incidence in patients with CHB[14]. Most of the studies describing the impact of treating CHB on the incidence of liver cancer evaluated the first generation drugs, specifically lamivudine and adefovir. There is less available data regarding the effect of the 3rd generation drugs, tenofovir and entecavir. One recent meta-analysis of patients with HBsAg seroclearance (n = 34,952) showed a significantly decreased risk for developing HCC in comparison to those with who did not seroconvert [risk ratio (RR) 0.34, 95% confidence interval (CI): 0.20-0.56, P < 0.001], but among those who seroconverted, 2.29% (95%CI: 1.19-4.37) still developed HCC[15].

    Adefovir and lamivudine

    Liaw et al.[3] published the only randomized clinical trial that addresses the benefits of using lamivudine in CHB patients with cirrhosis or advanced fibrosis proven by biopsy. Compared to the placebo group, the lamivudine group had a significant reduction in HCC, 7.4% vs. 3.9% respectively (HR 0.49, P = 0.047). Additionally, the group treated with lamivudine had a nearly 50% reduction in progression of disease (7.8% vs. 17.7%, HR 0.45, P = 0.001). As a result of the significant difference found between the 2 arms, the study was stopped prematurely after a mean duration of 32.4 months.

    The advantages of using the first-generation NAs to reduce HCC risk has since been supported in meta-analyses and systematic reviews. In a meta-analysis evaluating 5 studies that compared oral treatment to placebo, treatment with NAs was associated with 78% reduced incidence of HCC (RR 0.22, P < 0.001) irrespective of cirrhosis. Treatment with NAs has also been shown to benefit patients who developed treatment resistance (NA 3.3% vs. control 6.4%, RR 0.52, P = 0.04)[16]. Similar results were reported in a systematic review that assesses adefovir, lamivudine, and the combination of both vs. placebo in 3,881 CHB patients naive to treatment with NAs. Over a period of 42 months, HCC incidence was lower in treated patients (2.8%) compared to patients who were not treated (6.4%; P = 0.003)[17]. Another meta-analysis reported rates of HCC of 3.5% in lamivudine-treated CHB patients compared to 9.6% in CHB patients who were not treated, over a period of 4 years[18].

    Entecavir and tenofovir

    The introduction of the third generation NAs, tenofovir and entecavir, which both have a high genetic barrier to resistance, has led to further decreases in HCC incidence. A retrospective study comparing the incidence of HCC in entecavir-treated patients to a historical cohort of lamivudine-treated patients without rescue therapy in the event of resistance development was conducted in Japan. Propensity score matching was used to eliminate baseline differences and the authors found that entecavir-treated patients had a lower 5-year cumulative incidence of HCC compared to historical controls (3.7% vs. 13.7%, P < 0.001). The benefit of treatment was seen mainly in cirrhotic patients, 7% in the entecavir group vs. 39% in historic controls (P = 0.049) compared to the non-cirrhotic group, and 3.3% in the entecavir vs. 3% in controls (P > 0.05)[19]. In an observational study conducted by Wong et al.[20], there was also decreased incidence of HCC with entecavir treatment compared to historical controls, also significant only in cirrhotic patients (13.8% vs. 26.4%, P = 0.049). A similar observational study by Su et al.[21] of patients with cirrhosis demonstrated 5 year cumulative HCC incidence of 26.4% in the untreated historical cohort and 11.3% in the treated cohort with entecavir resulting in reduction of HCC risk by approximately 60% (HR 0.40, 95%CI 0.28-0.57). In another propensity score-matched study of Japanese patients (n = 234), Kumada et al.[22] determined that entecavir therapy significantly reduced HCC incidence; the 5- and 10-year cumulative incidence of HCC were 11.3% and 40% in untreated controls, respectively, compared to 2.7% and 3.3% in patients treated with entecavir. Long-term entecavir treatment has been shown to reduce fibrosis by more than 1 point by the Ishak fibrosis score in 88% of patients who were treated for 6 years[23]. A large retrospective study of Taiwanese patients (n = 21,595), assessed a cohort of NA-treated patients and a cohort of patients receiving hepatoprotective agents, but no NA treatment matched by propensity score. The 7-year incidence of HCC was significantly lower in the cohort treated with NA (7.3%), compared to the non-NA treated cohort (22.7%) (adjusted HR 0.37; P < 0.001). In this study, the benefits of NA therapy were noted among patients without (HR 0.27) cirrhosis in addition to patients with cirrhosis (HR 0.72)[24].

    A recent retrospective study conducted in Canada utilized the REACH-B scoring system to evaluate the risk of developing HCC among patients treated with NAs. A total of 322 patients were followed for a median of 3.2 years; median treatment duration with NAs was 3.4 years (interquartile range 1.6-5.9) and 80% of the patients were treated with tenofovir or entecavir. During the study period, 11 patients, 3.2%, developed HCC; 9 of these were Asian men. Cirrhosis was the strongest risk factor for HCC development (unadjusted risk 22-fold); patients with cirrhosis had an annual HCC incidence rate of 4.3% vs. 0.2% in patients without cirrhosis. Use of NAs reduced the risk of HCC development; based on the REACH-B model, there was a 50% relative reduction in HCC incidence with NA use, noted as early as 4 years after initiation of treatment[25]. The Chronic Hepatitis Cohort Study, a longitudinal study in the United States, recently evaluated the relationship between CHB therapy and HCC incidence in 2,671 patients. Patients were diagnosed with CHB between 1992 to 2011 and data were analyzed and collected over a 5-year period; 49% of the sample was Asian. Using propensity score matching and Cox regression analysis, the authors found that patients treated with antivirals had a lower risk of HCC than those who were not treated with antivirals (adjusted HR 0.39; 95%CI 0.27-0.56; P < 0.001), after adjusting for abnormal level of alanine aminotransferase (ALT). Like the Canadian study above, the observational, retrospective, multicenter cohort study ENUMERATE conducted in the United States used the REACH-B system to assess HCC risk in NA-treated patients. The study included 841 treatment-naïve CHB patients over an 8-year period who had received > 12 months of entacavir with a median follow-up of 4 years. Overall, HCC was diagnosed in 17 patients (2.6%): 8 patients had cirrhosis (13.1%) and developed HCC and 9 patients without cirrhosis (1.5%) developed HCC. In comparison to those who did not develop HCC, the patients with HCC were more likely to have cirrhosis (47.1% vs. 8.4%) and to be older (53 years vs. 47 years). Among patients who did not have cirrhosis, the observed HCC incidence was lower than the predicted incidence by the fourth year [standardized incidence ratio (SIR) 0.37; 95%CI 0.166-0.82]. By 8.2 years, the maximum follow-up time, the observed incidence of HCC was significantly lower than predicted for all patients (SIR 0.56; 95%CI 0.35-0.905)[26].

    In addition to reversing fibrosis, tenofovir therapy has been shown to decrease HCC risk. In the seminal study by Marcellin et al.[27], treatment with tenofovir for 5 years led to improvement in histology and regression of fibrosis regression (≥ 1 point decrease by Ishak scoring system) in 87% and 51% of the patients, respectively. Kim et al.[28] compared the observed HCC incidence among the 641 patients enrolled in 2 tenofovir registration trials to the incidence of HCC estimated by the REACH-B risk calculator. Starting at 3.3 years, divergence emerged and progressively widened between the predicted and observed incidence of HCC between the 2 groups. Furthermore, at latest follow-up (median of 5.52 years), the SIR between observed and predicted supporting that treatment with tenofovir is beneficial. A recent study conducted in Taiwan examined the efficacy and safety of treatment in NA-naive and NA-experienced patients with CHB; after 3 years of therapy, cumulative HCC incidence at 12, 24 and 36 months were 0%, 1.2%, and 4.8%, respectively, and no significant differences were found between NA-naive and NA-experienced patients in regards to HCC development[29].

    Impact of NA choice on HCC incidence

    In a study conducted in Korea, patients with compensated cirrhosis secondary to CHB, hepatitis B DNA < 2,000 IU/mL, and normal ALT had HCC incidence of nearly 10% over 5 years, but NA therapy reduced incidence to 5.9% for HBV patients treated with NAs; longer duration of treatment and virological response were associated with lower risk of HCC[30]. A recent multicenter study demonstrated a reduction of 77% in HCC incidence in those treated with NAs treatment compared to those who were untreated; this was adjusted for age, gender, ALT, and HBV DNA and was independent of the presence of cirrhosis[31].

    Several studies have also evaluated whether the choice of NA affects risk reduction of HCC. In a retrospective study of CHB patients with cirrhosis (n = 227, 104 with decompensated cirrhosis) who were followed over 21-36 months, Koklu et al.[32] showed the incidence of HCC to be 3%, 5%, and 8%, respectively, in the tenofovir, entacavir, and lamivudine groups. There was no significant difference found between the NA in the prevention of HCC. In a study of 355 treatment-naïve patients with CHB, 39.2% of whom had cirrhosis, who received entecavir or tenofovir, Idilman et al.[33] found that the cumulative incidence of HCC at 1 year was 3.3% and at 4 years was 7.3%. No significant difference was found between the 2 groups. A multicenter European study evaluated 1,756 Caucasian patients in an attempt to evaluate the impact of treatment with entecavir and/or tenofovir for 39 months on HCC occurrence. Overall, the 5-year cumulative probability of HCC was 8.7%. In patients without cirrhosis, the cumulative 5-year HCC rate was 3.7% compared to 17.5% in patients with cirrhosis and 36.3% in patients with decompensated cirrhosis[34]. In a recent review of NAs including lamivudine, tenofovir, and entecavir, Papatheodoridis et al.[35] concluded that no significant difference exists between agents in preventing HCC even in patients who were rescued after development of lamivudine resistance.

    A recent Greek analysis compared a cohort of patients treated with entecavir (n = 321), for a median duration of 40 months to a matched cohort of patients (n = 818), initially treated with lamivudine for a median duration of 60 months. Using multivariable Cox regression analysis, risk of HCC was independently associated with male gender (P = 0.011), older age (P < 0.001), and cirrhosis (P = 0.025); HCC risk was not associated with the choice of agent used, at least for the first 5 years[36]. In a Taiwanese population-based cohort study, 1,544 patients with active hepatitis due to HBV taking lamivudine, entecavir, tenofovir, or telbivudine over an 8-year period were evaluated for HCC risk and risk of mortality. For the propensity score matching, patients not treated with NAs (n = 1,544), were selected as the comparison group. As mentioned previously, the treated cohort had a significantly lower rate of HCC occurrence (6.0%; 95%CI 4.4%-7.9%) compared to the cohort not treated with NAs (8.5%; 95%CI 6.6%-10.6%; P = 0.0025). Overall mortality rate for the treated cohort was 6.9% (95%CI 5.3%-8.7%) compared to 9.4% for the untreated cohort (95%CI 7.7%-11.3%) (P = 0.0003). Cox regression analyses demonstrated that use of NAs use significantly reduced the risk of HCC (HR 0.64; 95%CI 0.45-0.93; P = 0.017) and overall mortality (HR 0.58; 95%CI 0.43-0.79; P < 0.001)[37].

    Finally, there is new evidence that treatment of CHB reduces mortality related to HCC and HCC recurrence in patients undergoing curative treatments[38]. Huang et al.[38] demonstrated antiviral therapy after liver resection to be an independent protective factor of late tumor recurrence (HR 0.348). Similar results were reported by Yin et al.[39] In a randomized controlled trial, antiviral therapy reduced both tumor recurrence (HR 0.48) and HCC-related death (0.26). In a study of Taiwanese patients undergoing resection (n = 4,569), those who received NA had significantly lower recurrence rate at 6 years compared to patients not treated with NAs (45.6% vs. 54.6% respectively) (P < 0.001). Additionally, the NA-treated group had lower mortality overall at 6 years (29% vs. 42.4%) (P < 0.001)[40]. In a recent meta-analysis including 8,204 patients status-post curative resection of HCC, high viral load was significantly associated with increased risk of recurrence, poorer disease-free survival and overall survival of HBV-related HCC after surgical resection. However, NA therapy significantly decreased the recurrence risk (RR 0.69; 95%CI 0.59-0.80; P < 0.001) and improved both disease-free (RR 0.70; 95%CI 0.58-0.83; P < 0.001) and overall survival (RR 0.46; 95%CI 0.32-0.68; P < 0.001) in these patients[41]. Clearly, surgical and medical treatment of CHB improves mortality due to HCC and reduces its recurrence.

    Limitations of the HCC predictor models

    Several HCC risk calculators have been proposed including the REACH-B based on a Taiwanese population, the Chinese-University-Hepatocellular carcinoma score (CU-HCC) score[42], and the GAG-HCC score, which incorporates age, gender, HBV DNA, presence of core promoter mutations and cirrhosis[43]. These models were developed in Asians and the application to other populations is unclear, though one study showed good performance in non-Asians[44]. The platelet, age, gender (PAGE-B score is based on platelet, age and gender and was developed to assess risk of HCC in Caucasians. Another limitation of these models is that they do not include a liver fibrosis assessment such as transient elastography. In addition, some models like the CU-HCC included 15% of HBV treated patients rather than all treatment naïve patients. It is questionable whether the HCC risk predictor models can be used in patients on HBV therapy, as therapy leads to viral suppression and may lead to fibrosis regression. In addition, the absence of the degree of HBV viral suppression in some models is a major limitation of the risk calculators[35].


    In patients with CHB, successful treatment can reduce but not eliminate the risk of developing HCC, regardless of the presence or absence of cirrhosis. Treatment of CHB can reverse fibrosis as demonstrated by studies involving the third-generation NAs tenofovir and entecavir, which have a high genetic barrier to resistance. Additionally, growing evidence supports that treatment of CHB reduces recurrence rates of HCC and HCC-related mortality in CHB patients who received curative treatments for HCC.

    Most data regarding chemoprevention is derived from studies using lamivudine and this significantly limits interpretation of the data. It is possible that the chemopreventative effect is more pronounced with the long term use of entecavir and tenofovir, which have a much lower risk of resistance with prolonged use when compared to lamivudine. Most of the studies evaluating the effect of chemoprevention are retrospective in nature, which is another major limitation. In other studies, the reduction of HCC incidence was not the primary outcome measured. Despite these limitations, results from medium-length follow up studies with entecavir and tenofovir and analyses of registration trials already suggest that treatment with these NAs have chemopreventive effects and reduce risk of HCC.

    Continued viral suppression is critical to minimize the risk of HCC development, although achieving viral suppression will not eliminate the risk of HCC, specifically in high-risk patients with advanced fibrosis or cirrhosis. In these situations, continuous surveillance for HCC is essential. Prospective studies which address the confounding factors such as gender, age, fibrosis stage. Finally, HCC screening algorithms are necessary to better elucidate the impact of chemoprevention on HCC development in HBV patients treated with the newer nucleos(t)ide agents.

    In summary, treatment of hepatitis B leads to decreased incidence of hepatocellular carcinoma in Asians and Caucasians regardless of the nucleos(t)ide used. Also, decreasing the HBV viral load, regardless of achieving seroconversion, results in decreased HCC incidence. Despite this reduction in HCC incidence, patients treated with nucleos(t)ides still need to undergo liver cancer screening. Several HCC predictor models have been developed, but as of now, there are limitations in applicability.


    Authors’ contributions

    Project conception: W.S. Ayoub, P. Martin, P.D. Jones

    Literature review, manuscript drafting and critical revision: W.S. Ayoub, F. Dailey, P. Martin, P.D. Jones

    Financial support and sponsorship


    Conflicts of interest

    Walid S. Ayoub, Francis Dailey, Paul Martin, Patricia D. Jones declare that they have no conflicts of interest.

    Patient consent

    Not applicable.

    Ethics approval

    This article does not contain any studies with human or animal subjects performed by any of the authors.


    © The Author(s) 2017.


    • 1. Bruix J, Sherman M; American Association for the Study of Liver Disease. Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020-2.

    • 2. Chang MH, You SL, Chen CJ, Liu CJ, Lai MW, Wu TC, Wu SF, Lee CM, Yang SS, Chu HC, Wang TE, Chen BW, Chuang WL, Soon MS, Lin CY, Chiou ST, Kuo HS, Chen DS; Taiwan Hepatoma Study Group. Long-term effects of hepatitis B immunization of infants in preventing liver cancer. Gastroenterology 2016;151:472-80.e1.

    • 3. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-31.

    • 4. Vlachogiannakos J, Papatheodoridis G. Hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy. World J Gastroenterol 2013;19:8822-30.

    • 5. Kao JH, Liu CJ, Jow GM, Chen PJ, Chen DS, Chen BF. Fine mapping of hepatitis B virus pre-S deletion and its association with hepatocellular carcinoma. Liver Int 2012;32:1373-81.

    • 6. Tseng TC, Liu CJ, Yang HC, Su TH, Wang CC, Chen CL, Kuo SF, Liu CH, Chen PJ, Chen DS, Kao JH. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 2012;142:1140-9.e3; quiz e13-4.

    • 7. Moon JC, Kim SH, Kim IH, Lee CH, Kim SW, Lee SO, Lee ST, Kim DG. Disease progression in chronic hepatitis B patients under long-term antiviral therapy. Gut Liver 2015;9:395-404.

    • 8. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008;48:335-52.

    • 9. Raffetti E, Fattovich G, Donato F. Incidence of hepatocellular carcinoma in untreated subjects with chronic hepatitis B: a systematic review and meta-analysis. Liver Int 2016;36:1239-51.

    • 10. Marcellin P, Buti M, Krastev Z, de Man RA, Zeuzem S, Lou L, Gaggar A, Flaherty JF, Massetto B, Lin L, Dinh P, Subramanian GM, McHutchison JG, Flisiak R, Gurel S, Dusheiko GM, Heathcote EJ. Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate. J Hepatol 2014;61:1228-37.

    • 11. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661-2.

    • 12. Gish RG, Chang TT, Lai CL, de Man R, Gadano A, Poordad F, Yang J, Brett-Smith H, Tamez R. Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naive HBeAg-positive patients with chronic hepatitis B. J Viral Hepat 2010;17:16-22.

    • 13. Ayoub WS, Keeffe EB. Review article: current antiviral therapy of chronic hepatitis B. Aliment Pharmacol Ther 2011;34:1145-58.

    • 14. Triolo M, Della Corte C, Colombo M. Impact of HBV therapy on the incidence of hepatocellular carcinoma. Liver Int 2014;34 Suppl 1:139-45.

    • 15. Liu F, Wang XW, Chen L, Hu P, Ren H, Hu HD. Systematic review with meta-analysis: development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis B surface antigen seroclearance. Aliment Pharmacol Ther 2016;43:1253-61.

    • 16. Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2008;28:1067-77.

    • 17. Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol 2010;53:348-56.

    • 18. Singal AK, Salameh H, Kuo YF, Fontana RJ. Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 2013;38:98-106.

    • 19. Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, Akuta N, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013;58:98-107.

    • 20. Wong GL, Chan HL, Mak CW, Lee SK, Ip ZM, Lam AT, Iu HW, Leung JM, Lai JW, Lo AO, Chan HY, Wong VW. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology 2013;58:1537-47.

    • 21. Su TH, Hu TH, Chen CY, Huang YH, Chuang WL, Lin CC, Wang CC, Su WW, Chen MY, Peng CY, Chien RN, Huang YW, Wang HY, Lin CL, Yang SS, Chen TM, Mo LR, Hsu SJ, Tseng KC, Hsieh TY, Suk FM, Hu CT, Bair MJ, Liang CC, Lei YC, Tseng TC, Chen CL, Kao JH; C-TEAM study group and the Taiwan Liver Diseases Consortium. Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients. Liver Int 2016;36:1755-64.

    • 22. Kumada T, Toyoda H, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Niinomi T, Yasuda S, Andou Y, Yamamoto K, Tanaka J. Effect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients: a propensity score analysis. J Hepatol 2013;58:427-33.

    • 23. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W, Goodman Z, Chi YC, Zhang H, Hindes R, Iloeje U, Beebe S, Kreter B. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010;52:886-93.

    • 24. Wu CY, Lin JT, Ho HJ, Su CW, Lee TY, Wang SY, Wu C, Wu JC. 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;147:143-51.e5.

    • 25. Coffin CS, Rezaeeaval M, Pang JX, Alcantara L, Klein P, Burak KW, Myers RP. The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy. Aliment Pharmacol Ther 2014;40:1262-9.

    • 26. Gordon SC, Lamerato LE, Rupp LB, Li J, Holmberg SD, Moorman AC, Spradling PR, Teshale EH, Vijayadeva V, Boscarino JA, Henkle EM, Oja-Tebbe N, Lu M; CHeCS Investigators. Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population. Clin Gastroenterol Hepatol 2014;12:885-93.

    • 27. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, Germanidis G, Flaherty JF, Schall RA, Bornstein JD, Kitrinos KM, Subramanian GM, McHutchison JG, Heathcote EJ. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013;381:468-75.

    • 28. Kim W, Berg T, Loomba R, Aguilar Schall R, Dinh P, Yee L, Martins E, Flaherty J, Gurel S, Buti M. Long term tenofovir disoproxil fumarate (TDF) therapy and the risk of hepatocellular carcinoma. J Hepatol 2013;58:S19.

    • 29. Wang HM, Hung CH, Lee CM, Lu SN, Wang JH, Yen YH, Kee KM, Chang KC, Tseng PL, Hu TH, Chen CH. Three-year efficacy and safety of tenofovir in nucleos(t)ide analog-naive and nucleos(t)ide analog-experienced chronic hepatitis B patients. J Gastroenterol Hepatol 2016;31:1307-14.

    • 30. Sinn DH, Lee J, Goo J, Kim K, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Yoo BC, Paik SW. Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load. Hepatology 2015;62:694-701.

    • 31. Lin D, Yang HI, Nguyen N, Hoang J, Kim Y, Vu V, Le A, Chaung K, Nguyen V, Trinh H, Li J, Zhang J, Hsing A, Chen CJ, Nguyen MH. Reduction of chronic hepatitis B-related hepatocellular carcinoma with anti-viral therapy, including low risk patients. Aliment Pharmacol Ther 2016;44:846-55.

    • 32. Koklu S, Tuna Y, Gulsen MT, Demir M, Koksal AS, Kockar MC, Aygun C, Coban S, Ozdil K, Ataseven H, Akin E, Purnak T, Yuksel I, Ataseven H, Ibis M, Yildirim B, Nadir I, Kucukazman M, Akbal E, Yuksel O, Basar O, Alkan E, Baykal O. Long-term efficacy and safety of lamivudine, entecavir, and tenofovir for treatment of hepatitis B virus-related cirrhosis. Clin Gastroenterol Hepatol 2013;11:88-94.

    • 33. Idilman R, Gunsar F, Koruk M, Keskin O, Meral CE, Gulsen M, Elhan AH, Akarca US, Yurdaydin C. Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-naive chronic hepatitis B patients in the real-world setting. J Viral Hepat 2015;22:504-10.

    • 34. Papatheodoridis GV, Dalekos GN, Yurdaydin C, Buti M, Goulis J, Arends P, Sypsa V, Manolakopoulos S, Mangia G, Gatselis N, Keskin O, Savvidou S, Hansen BE, Papaioannou C, Galanis K, Idilman R, Colombo M, Esteban R, Janssen HL, Lampertico P. Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir. J Hepatol 2015;62:363-70.

    • 35. Papatheodoridis GV, Chan HL, Hansen BE, Janssen HL, Lampertico P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J Hepatol 2015;62:956-67.

    • 36. Papatheodoridis GV, Manolakopoulos S, Touloumi G, Nikolopoulou G, Raptopoulou-Gigi M, Gogos C, Vafiadis-Zouboulis I, Karamanolis D, Chouta A, Ilias A, Drakoulis C, Mimidis K, Ketikoglou I, Manesis E, Mela M, Hatzis G, Dalekos GN, Grp HGS. Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort. J Viral Hepat 2015;22:120-7.

    • 37. Wang JP, Kao FY, Wu CY, Hung YP, Chao Y, Chou YJ, Li CP. Nucleos(t)ide analogues associated with a reduced risk of hepatocellular carcinoma in hepatitis B patients: a population-based cohort study. Cancer 2015;121:1446-55.

    • 38. Huang G, Lau WY, Wang ZG, Pan ZY, Yuan SX, Shen F, Zhou WP, Wu MC. Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial. Ann Surg 2015;261:56-66.

    • 39. Yin J, Li N, Han Y, Xue J, Deng Y, Shi J, Guo W, Zhang H, Wang H, Cheng S, Cao G. 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 2013;31:3647-55.

    • 40. Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, Wu MS, Lin JT. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA 2012;308:1906-14.

    • 41. Zhou Y, Zhang Z, Zhao Y, Wu L, Li B. Antiviral therapy decreases recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection: a meta-analysis. World J Surg 2014;38:2395-402.

    • 42. Wong VW, Chan SL, Mo F, Chan TC, Loong HH, Wong GL, Lui YY, Chan AT, Sung JJ, Yeo W, Chan HL, Mok TS. Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers. J Clin Oncol 2010;28:1660-5.

    • 43. Yuen MF, Tanaka Y, Fong DY, Fung J, Wong DK, Yuen JC, But DY, Chan AO, Wong BC, Mizokami M, Lai CL. Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B. J Hepatol 2009;50:80-8.

    • 44. Abu-Amara M, Cerocchi O, Malhi G, Sharma S, Yim C, Shah H, Wong DK, Janssen HL, Feld JJ. The applicability of hepatocellular carcinoma risk prediction scores in a North American patient population with chronic hepatitis B infection. Gut 2016;65:1347-58.


    Cite This Article

    Ayoub WS, Dailey F, Martin P, Jones PD. The impact of nucleos(t)ide analog therapy in hepatitis B on the incidence of hepatocellular carcinoma: an update including recent literature findings. Hepatoma Res 2017;3:302-308.



    Download and Bookmark


    Download PDF Add to Bookmark

    Share This Article

    Article Access Statistics

    Quantities of Full-Text Views Each Month

    Quantities of PDF Downloads Each Month


    Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at

    Article Access Statistics

    • Viewed: 2474
    • Downloaded: 624
    • Cited: Crossref0

    Share This Article

    Recommended Articles

    Copyright © 2021 OAE Publishing Inc. All Rights Reserved.