Entecavir in the treatment of chronic hepatitis B virus infection

INTRODUCTION — Entecavir is an orally administered cyclopentyl guanosine analog that is used for treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of active disease (based on elevated serum aminotransferases or histology), or advanced fibrosis or cirrhosis based on histology, noninvasive tests (eg, elastography), or clinical findings (eg, decompensation).

This topic review will discuss the use of entecavir for treatment of chronic hepatitis B virus infection. A general approach to the treatment of patients with hepatitis B (including other treatment options) is presented separately. (See "Hepatitis B virus: Overview of management".)

THE EFFICACY OF ENTECAVIR IN DIFFERENT PATIENT POPULATIONS

Treatment-naïve patients

HBeAg-positive chronic hepatitis — Treatment with entecavir achieves hepatitis B e antigen (HBeAg) seroconversion in about 20 percent of patients with HBeAg-positive hepatitis B virus (HBV) who have not previously been treated with nucleoside(tide) analogs [1-6]. In addition, one-year treatment is associated with a 5 to 7 log(10) reduction in mean HBV DNA levels and corresponding improvement in liver histology. The rate of virologic resistance is around 1 percent with up to five years of follow-up.

Versus lamivudine — A multinational trial included 715 patients with HBeAg-positive chronic HBV who were randomly assigned to entecavir (0.5 mg daily) or lamivudine (100 mg daily) for 48 weeks [2]. Patients were eligible if they had HBV DNA levels ≥3 mEq/mL (approximately 600,000 international units/mL), a serum alanine transaminase (ALT) ≥1.3 times the upper limit of normal, compensated liver disease, and had no or <12 weeks of nucleoside(t)e therapy for HBV previously.

At week 48, HBeAg seroconversion was observed in 21 percent of the entecavir group and 18 percent of the lamivudine group (table 1 and table 2). Serum HBV DNA decreased from baseline by an average of 6.86 log(10) compared with 5.39 log(10) in the lamivudine group. Suppression of HBV DNA to less than 0.7 mEq/mL (approximately 140,000 international units/mL) and normalization of serum ALT were observed significantly more often in the entecavir group (91 versus 65 percent and 78 versus 70 percent, respectively). Serum HBV DNA was undetectable by PCR assay in 67 percent of the entecavir group compared with 36 percent in the lamivudine group.

Histologic improvement (defined as ≥2 point reduction in the Knodell necroinflammatory score) was observed significantly more often in the entecavir group (72 versus 62 percent). Serious adverse events were described in 7 percent of patients in both groups.

Treatment was extended until HBeAg loss or up to 96 weeks in a subset of patients who remained HBeAg positive but had HBV DNA less than 0.7 mEq/mL (ie, less than approximately 140,000 international units/mL) at week 48 [3]. At week 96 or earlier (for patients who achieved HBeAg loss before week 96), HBV DNA was undetectable in a larger proportion of entecavir versus lamivudine treated patients (80 versus 39 percent). Normalization of ALT was observed in 87 versus 79 percent, and HBeAg seroconversion in 31 versus 25 percent. The safety profile was similar to lamivudine throughout the observation period.

Analysis of cumulative responses up to week 96 of all patients originally enrolled into the study found that the proportion of patients achieving HBeAg seroconversion were similar (31 versus 25 percent). However, this analysis did not take into account HBeAg reversion after treatment was stopped.

A follow-up report described a subset of 146 patients who received continuous therapy for up to five years [4]. The group was comprised mainly of virologic responders but also included 19 patients who failed to respond during the first year of treatment. All patients received entecavir 1 mg daily from year 3 onward. During years 3, 4, and 5, an increasing proportion of patients achieved and maintained HBV DNA levels <300 copies/mL (approximately 60 international units/mL) (94 percent by year 5). In addition, 33 additional patients (23 percent) achieved HBeAg seroconversion, and two patients (1.4 percent) lost hepatitis B surface antigen (HBsAg) during continued treatment. These data confirm that continued treatment can result in late HBeAg seroconversion in some patients. In a separate follow-up report that focused on 40 HBeAg-positive patients, all of whom achieved HBV DNA levels of <300 copies/mL (approximately 60 international units/mL) and most of whom had normal aminotransferase levels, treatment with entecavir for five years was associated with a decrease in inflammation as well as fibrosis scores [5]. However, whether these results can be generalized is uncertain since this report included fewer than 10 percent of the original cohort.

Versus adefovir — Entecavir is associated with a greater degree of reduction of HBV DNA than adefovir. An open-label, comparative trial included 69 antiviral-naïve patients who were randomly assigned to entecavir (0.5 mg daily) or adefovir (10 mg daily) for a minimum of 52 weeks [7]. The mean HBV DNA change from baseline to week 48 was significantly greater with entecavir (-6.23 versus -4.42 log(10) copies/mL). In addition, significantly more patients receiving entecavir achieved undetectable (<300 copies/mL or approximately 60 international units/mL) HBV DNA levels by PCR between weeks 2 to 48. At 48 weeks, only 3 percent of entecavir treated patients had HBV DNA of 10(5) copies/mL (approximately 20,000 international units/mL) or more compared with 47 percent of adefovir treated patients. These data confirmed that entecavir has more potent antiviral activity than adefovir. Adverse events were similar.

Versus tenofovir — Entecavir and tenofovir appear to have similar efficacy in treatment-naïve patients during the first year of therapy. Meta-analyses comparing these agents have found no significant differences in HBV DNA suppression, ALT decline, HBeAg seroconversion, and toxicity (eg, nephrotoxicity and hypophosphatemia) [8,9]. However, there are no high-quality data directly comparing the long-term efficacy and safety of these agents.

Role of combination therapy — There is no clear benefit of combination therapy with entecavir plus pegylated interferon among HBeAg-positive patients with chronic HBV infection.

●In one randomized, open-label study of 218 treatment-naïve patients from China, patients received 48 weeks of pegylated interferon alfa-2a alone, or with 24 weeks of entecavir administered prior to or after peginterferon was initiated [10]. Rates of HBeAg seroconversion 24 weeks post-treatment were similar in all three groups: 33 percent in the monotherapy group, 25 percent in the entecavir add-on group, and 26 percent in the entecavir pretreatment group.

●In another randomized, open-label study, 175 HBeAg-positive patients received entecavir monotherapy or entecavir plus pegylated interferon alfa-2a added on between weeks 24 and 48 [11]. There was a nonsignificant increase in response to therapy (defined as HBeAg loss and HBV DNA <200 IU/mL) at week 48 in the add-on compared with the monotherapy group (19 versus 10 percent, respectively).

In addition, the use of tenofovir disoproxil plus entecavir does not offer any benefit compared with entecavir monotherapy for most treatment-naïve patients. However, some studies suggest this combination may be effective in treatment-naïve patients with high baseline viremia or in patients who have experienced treatment failure to sequential courses of nucleos(t)ide analogue therapy and/or have multi-drug resistant HBV. The use of entecavir in combination with tenofovir is discussed in separate topic reviews. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'In combination with other drugs' and "Hepatitis B virus: Overview of management", section on 'While receiving tenofovir or entecavir'.)

HBeAg-negative chronic hepatitis — A multinational trial included 648 patients with HBeAg-negative chronic HBV who were randomly assigned to entecavir (0.5 mg daily) or lamivudine (100 mg daily) for up to 96 weeks [12]. Patients were eligible if they had HBV DNA ≥0.7 mEq/mL (approximately 140,000 international units/mL), and ALT level ≥1.3 times the upper limit of normal, compensated liver disease, and had no or <12 weeks of nucleoside(tide) therapy for HBV previously.

The primary efficacy endpoint, histologic improvement, defined as a ≥2 point reduction in the Knodell necroinflammatory score at 48 weeks, was observed significantly more often in the entecavir group (70 versus 61 percent) (table 1 and table 2). The mean reduction in HBV DNA was significantly greater in the entecavir group, and undetectable HBV DNA by PCR occurred significantly more often (90 versus 72 percent). Serum HBV DNA decreased by 5.04 log(10) in the entecavir group compared with 4.53 log(10) in the lamivudine group. The proportion of patients with ALT normalization was significantly higher in the entecavir group (90 versus 72 percent). Serious adverse events were comparable (6 versus 8 percent). Long-term responses are unclear because most patients were taken off treatment at the end of year one. In a follow-up report, most responders who discontinued treatment after 48 weeks had a relapse of HBV DNA within 24 weeks [13]. In a separate follow-up report that included 17 HBeAg-negative patients, all of whom achieved HBV DNA levels of <300 copies/mL (approximately 60 international units/mL) and most of whom had normal aminotransferase levels, treatment with entecavir for five years was associated with a decrease in inflammation as well as fibrosis scores [5].

Multiple prospective and retrospective cohort studies assessing the efficacy and safety of entecavir in nucleos(t)ide-naïve chronic HBV patients that would not have been included in the initial phase III trials have also demonstrated high rates of virologic and serologic responses and a low incidence of resistance [14-16].

Treatment-experienced patients

Patients previously treated with lamivudine — We typically avoid entecavir in patients who have been previously treated with lamivudine monotherapy. For such patients, tenofovir is generally preferred. (See "Tenofovir and adefovir for the treatment of chronic HBV infection".)

This is particularly important for those with confirmed lamivudine-resistant virus (see 'Resistance' below), because the efficacy of entecavir (even when dosed at 1 mg per day) is lower, and the risk of developing entecavir resistance is greater (up to 50 percent after five years), compared with those who are lamivudine-naïve [17-19]. The recommendation to avoid entecavir in patients with lamivudine resistance is supported by both the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) [20,21].

A detailed discussion of the management of patients with lamivudine-resistant HBV is found elsewhere. (See "Hepatitis B virus: Overview of management", section on 'Persistent viremia/breakthrough infection'.)

Patients previously treated with adefovir — Entecavir can be used in patients who have resistance to adefovir but should not be used in patients who have prior resistance to lamivudine. Although this recommendation is supported by both the AASLD and the EASL [20,21], the use of entecavir in this setting is based upon limited data.

Special populations

Patients with HIV — Experience with entecavir in patients with HIV and HBV is limited. Although the original package insert for entecavir indicated no anti-HIV activity by in vitro testing at clinically relevant concentrations, a one-log drop in HIV RNA was reported in three separate patients who were taking entecavir monotherapy. In one of these patients, there was selection of a lamivudine-resistant M184V HIV variant [22]. Data from this study and subsequent studies show that entecavir should not be used in patients with HIV and HBV who are not receiving fully suppressive antiretroviral regimens. (See "Treatment of chronic hepatitis B in patients with HIV".)

Severe exacerbation — Antiviral therapy should be initiated as soon as possible in patients with severe exacerbations. Given the need for long-term therapy, we recommend entecavir or tenofovir. Several studies have shown that entecavir is safe and effective in the management of severe exacerbations of chronic HBV [23-25]. Interferon should not be used in this setting. More detailed information on patient management is presented elsewhere. (See "Hepatitis B virus: Overview of management", section on 'Choice of initial agent'.)

Decompensated cirrhosis — In patients with decompensated cirrhosis, the virologic and clinical outcomes with entecavir are comparable to tenofovir and better than adefovir and lamivudine. These findings are highlighted in the following studies:

●A meta-analysis of 13 trials that included 873 patients compared entecavir with lamivudine for the treatment of HBV-related decompensated cirrhosis [26]. Entecavir produced significantly lower HBV DNA levels and significantly less drug resistance (0.3 versus 14.3 percent) as compared with lamivudine. Entecavir also resulted in nonsignificantly greater HBeAg seroconversion (32 versus 25 percent at 48 weeks) and lower mortality (6.4 versus 7.9 percent). Both drugs significantly improved liver function, and both were safe and well tolerated.

●A randomized, open-label study compared entecavir (1 mg daily) with adefovir (10 mg daily) in 191 patients with HBV and decompensated cirrhosis for up to 96 weeks [27]. The entecavir group had a greater decline in HBV DNA levels and was more likely to achieve an HBV DNA level of <300 copies/mL (approximately 60 international units/mL; 57 versus 20 percent at week 48). About two-thirds of patients in both groups showed either improvement or stabilization in Child-Turcotte-Pugh status. Adverse events were similar between the groups.

●A phase II randomized double-blind study evaluated safety in 112 patients with decompensated liver disease who were assigned to treatment with tenofovir, tenofovir plus emtricitabine, or entecavir [28]. Tenofovir and entecavir were both well tolerated and associated with similar improvements in virological, biochemical, and clinical features.

●One study included 70 treatment-naïve patients who received entecavir (0.5 mg daily) for one year [29]. During the course of follow-up, 15 patients dropped out (nine because of death or the need for liver transplantation, and six were lost to follow-up). Of the remaining 55 patients, 49 percent had improvement in Child-Turcotte Pugh score of ≥2 points. On intention-to-treat analysis, 92 percent became HBV DNA negative, and 54 percent lost HBeAg. Adverse events were not discussed.

●A retrospective cohort study compared clinical outcomes in 482 entecavir-treated and 69 treatment-naïve patients (ie, historical controls who were untreated) with cirrhosis [30]. Entecavir-treated patients who achieved viral suppression had a reduced risk of all clinical outcomes (hazard ratio [HR] 0.51; 95% CI 0.34-0.78), including hepatocellular carcinoma and mortality (liver-related and all-cause mortality).

Although entecavir is well tolerated in most patients with cirrhosis, entecavir can result in severe lactic acidosis when used in patients with decompensated cirrhosis [31]. Lactic acidosis may be a class effect of nucleosides and/or related to sepsis, which occurs commonly in hospitalized patients with decompensated cirrhosis. (See 'Safety' below and "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors", section on 'Hyperlactatemia and lactic acidosis'.)

Patients with minimally elevated ALT levels — Guidelines for the management of chronic HBV recognize that the degree of elevation of serum aminotransferases is predictive of the likelihood of response. Patients with low alanine transaminase (ALT) levels who are in the immune tolerant phase of infection tend to respond less well than those with elevated ALT levels. The indications for treatment of chronic HBV are discussed separately. (See "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy'.)

The efficacy of entecavir in patients with a low ALT level has not been extensively studied. However, a subset analysis that included 336 patients who had been treated as part of the phase III trial of entecavir and whose ALT was 1.3 to 2 times the upper limit of normal found that responses among HBeAg-negative patients were similar to those with higher ALT levels, while they were significantly lower in HBeAg-positive patients [32].

While these data suggest a potential benefit of treatment in patients with minimally elevated ALT, most patients will require many years of treatment to achieve the desired therapeutic endpoint. More studies are needed to determine whether the benefits of initiating treatment in patients with minimally elevated ALT on clinical outcomes are superior to deferring treatment until patients have higher ALT (eg, >2 times upper limit of normal), particularly in HBeAg-positive patients. Until further data are available, the decision to initiate treatment for patients with mildly elevated ALT levels should be individualized and will be influenced by the patient’s age, HBV DNA level, and severity of liver disease [20]. (See "Hepatitis B virus: Overview of management".)

RESISTANCE — Entecavir monotherapy is associated with a low rate of drug resistance in nucleoside-naïve patients (approximately 1 percent after five years treatment), but a high rate of resistance in lamivudine-refractory patients (approximately 50 percent after five years of treatment).

●No resistance was observed after 48 weeks of treatment in the two large multinational trials of nucleoside-naïve patients described above [2,12]. (See 'HBeAg-positive chronic hepatitis' above and 'HBeAg-negative chronic hepatitis' above.)

●A report from the manufacturer updated their resistance analysis in patients who had received up to five years of treatment [17]. In nucleoside-naïve patients, genotypic resistance and genotypic resistance associated with virologic breakthrough were observed in 1.2 and 0.8 percent, respectively. However, these rates may be artificially low because some nonresponders were excluded from the analysis and, in some patients, the entecavir dose was higher (ie, 1 mg daily) than commonly used in nucleoside-naïve patients (0.5mg daily). By contrast, genotypic resistance rates were much higher in patients with lamivudine resistance; in such patients, the five-year cumulative probability of genotypic resistance to entecavir and genotypic resistance associated with virologic breakthrough were 51 and 43 percent, respectively.

●Resistance was observed in only 0.4 percent of patients in a study of 474 nucleoside-naïve patients (47 percent hepatitis B e antigen [HBeAg] positive) followed for four years [33].

●In a series of 161 chronic hepatitis B patients receiving entecavir monotherapy, 43 had previously been treated with lamivudine [19]. Patients with lamivudine-resistant mutations at the start of entecavir monotherapy had a reduced probability of achieving a virologic response compared with lamivudine-naïve patients (HR 0.14; 95% CI 0.04-0.58).

●In another study, 50 patients with compensated chronic hepatitis B virus (HBV; 80 percent HBeAg positive) were switched to entecavir after developing adefovir-resistant mutations during adefovir monotherapy for lamivudine-refractory HBV [34]. Only 22 percent of patients achieved a complete virologic response (defined as HBV DNA <60 international units/mL) after 12 months.

When resistance to entecavir does develop, it appears to occur through a two-hit mechanism. Initially, mutants that are resistant to lamivudine (rtM204V/I) are selected because they are less sensitive to entecavir. During continued treatment, additional mutations at rtI169, rtT184, rtS202, and/or rtM250 are selected [35-37]. Entecavir resistant strains appear to be sensitive to adefovir and to tenofovir [37].

SAFETY — Overall, entecavir is well tolerated [38-41]. Adverse events were infrequently observed in a study of 1051 patients who were exposed to entecavir for a median of 3.5 years [38]. In this study:

●Four percent of adverse events were considered attributable to entecavir.

●Most adverse events were considered to be mild to moderate and included headache, upper respiratory tract infection, cough, nasopharyngitis, fatigue, and upper abdominal pain.

●On-treatment alanine transaminase (ALT) flares occurred in 3 percent of patients.

●One percent of patients discontinued treatment due to an adverse event (compared with 4 percent in lamivudine-treated patients).

Severe lactic acidosis has been reported in a case series of patients with advanced cirrhosis (MELD score ≥20) [31]. Lactic acid level was not monitored in several trials of entecavir in patients with decompensated cirrhosis, but clinical manifestations suggestive of severe lactic acidosis were not observed. Entecavir should be used with caution in patients with decompensated liver disease and always be adjusted for creatinine clearance. (See 'Dose' below.)

Studies in mice found an increased risk of lung adenomas (at exposures 3 to 40 times those in humans). In addition, hepatocellular carcinomas were increased in male mice, while brain gliomas were induced in male and female rats. However, increased risks of cancers have not been observed in studies of patients who have received long-term treatment with entecavir. In one trial that compared 6216 patients who received entecavir with 6162 patients who received standard of care hepatitis B virus (HBV) nucleos(t)ide analog therapy and followed them for up to 10 years, there were no differences in hepatocellular carcinoma or other malignant neoplasms [42].

PREGNANCY — We do not recommend the use of entecavir during pregnancy. Teratogenic effects have been observed in animal studies. A detailed discussion on the management of hepatitis B virus in pregnancy is found elsewhere. (See "Hepatitis B and pregnancy".)

DOSE — The recommended dose of entecavir is 0.5 mg daily for most nucleoside-naïve patients. A higher dose (1 mg) should be administered to patients with decompensated liver disease. The dose of entecavir should be adjusted in patients with a creatinine clearance <50 mL/min, as well as those on hemodialysis or continuous ambulatory peritoneal dialysis as follows:

●CrCl 30 to 49 mL/minute: Administer 50 percent of usual dose daily or administer the normal dose every 48 hours

●CrCl 10 to 29 mL/minute: Administer 30 percent of usual dose daily or administer the normal dose every 72 hours

●CrCl <10 mL/minute (including hemodialysis and CAPD): Administer 10 percent of usual dose daily or administer the normal dose every 7 days; administer after hemodialysis

VIROLOGIC RESPONSE TO THERAPY — For patients on entecavir, the American Association for the Study of Liver Disease (AASLD) considers an initial virologic response as an undetectable hepatitis B virus (HBV) DNA after 96 weeks of treatment [20]. Although most hepatitis B e antigen (HBeAg)-negative patients have undetectable HBV DNA after 48 weeks of treatment, some HBeAg-positive patients with high baseline HBV DNA may remain viremic at week 96. However, entecavir-resistant virus rarely occurs in treatment-naïve patients (see 'Resistance' above). As examples:

●In a multicenter cohort study that included 175 nucleoside-naïve patients on entecavir, 36 (21 percent) had a detectable viral load at 48 weeks (defined by the investigators as an HBV DNA >80 international units/mL) [14]. Of these 36 patients, 29 (81 percent) achieved an undetectable HBV DNA by approximately three years without modifications in their regimen or the development of resistance.

●Patients from six phase II and III clinical studies that evaluated the safety and efficacy of entecavir were monitored for resistance through year 5 [17]. In nucleoside-naïve patients, the cumulative probability of genotypic entecavir resistance was approximately 1 percent, even though 10 percent of patients had detectable HBV DNA (ie, ≥300 copies/mL or ≥60 international units/mL) at 48 weeks.

●In a retrospective study of 1254 treatment-naïve individuals on entecavir, most had a satisfactory response to therapy. Of the 16 primary nonresponders (using 2009 AASLD-based criteria), all achieved a virologic response (to <15 international units/mL) by 54 months without altering therapy [43].

The approach to patient monitoring and the management of patients with persistent viremia are presented separately. (See "Hepatitis B virus: Overview of management", section on 'Monitoring on therapy' and "Hepatitis B virus: Overview of management", section on 'Persistent viremia/breakthrough infection'.)

OPTIMAL DURATION OF THERAPY — We determine the optimal duration of therapy for patients with chronic hepatitis B virus (HBV) based upon their hepatitis B e antigen (HBeAg) status as well as the presence or absence of cirrhosis. These issues are discussed elsewhere in detail. (See "Hepatitis B virus: Overview of management", section on 'Duration and treatment endpoints'.)

RISK OF RELAPSE AFTER DISCONTINUING ENTECAVIR — Patients who discontinue treatment with entecavir must be monitored closely for relapse regardless of their hepatitis B e antigen (HBeAg) status [44-48]. As examples:

●In a retrospective study of 169 individuals who were treated with entecavir for a median 181 weeks, 35 patients with a virologic response discontinued treatment [45]. Nine of the patients who discontinued treatment (26 percent) had virologic relapse. All of those who relapsed were HBeAg positive at baseline and had loss of HBeAg prior to treatment discontinuation. Relapse occurred after a median of 48 weeks off of treatment.

●A study of 95 HBeAg-negative individuals who discontinued entecavir treatment after a median of 721 days found that a clinical relapse occurred in 45 percent of patients; most relapses occurred more than six months after stopping entecavir [46]. A low baseline hepatitis B virus (HBV) DNA (ie, ≤2x10⁵ international units/mL) was the only independent predictor of a sustained response; however, 29 percent of patients with a lower baseline HBV DNA still experienced relapse.

Virological relapses appear to occur later in both HBeAg-positive and HBeAg-negative patients who discontinue therapy with entecavir compared with tenofovir, though the overall rates of virologic and clinical relapse are similar [47-49]. In a prospective observational study of 100 patients discontinuing tenofovir or entecavir after three years, the risks of virologic and clinical relapse were significantly higher at three months in those receiving tenofovir versus entecavir (53 versus 6 percent and 15 versus 2 percent, respectively); however, relapse rates at 12 and 24 months were comparable [49]. As an example, at 24 months, cumulative rates of virologic and clinical relapse in patients who discontinued tenofovir and entecavir were 72 versus 65 percent and 41 versus 46 percent, respectively. In this study, the total duration of treatment and the duration of consolidation treatment were not predictors of relapse.

For individuals who experience a virologic relapse, we use the same criteria for reinitiating therapy as we do when initiating therapy for the first time. (See "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy'.)

EFFECT ON LONG-TERM OUTCOMES — Entecavir is associated with improved long-term outcomes. In a cohort study that included 1951 White European patients with chronic hepatitis B virus (HBV), overall eight-year survival was 94 percent in patients who received at least 12 months of entecavir or tenofovir [50], which is similar to that of the general population. In addition, one study found there was a significant decrease in the risk of developing hepatocellular carcinoma (HCC) in patients with compensated cirrhosis who received at least five years of therapy, with a decrease from 3.2 percent per year during the first five years to 1.6 percent per year between years 5 and 8 [51]. All HCCs occurred in patients older than 50 years of age at the start of entecavir or tenofovir. Factors that were independently associated with a higher risk of HCC after year 5 included older age, lower platelet count at baseline and at year 5, and liver stiffness ≥12 kPa (based on transient elastography) at year 5. In this study, no change in the incidence of HCC after year 5 was observed in patients who did not have cirrhosis pretreatment; however, it is possible that a longer duration of treatment is needed to show a change since the incidence of HCC is lower in these patients.

Studies evaluating the risk of HCC in patients receiving entecavir versus tenofovir have demonstrated conflicting results [52-54]. Some studies have found a lower incidence of HCC in patients receiving tenofovir compared to entecavir, despite propensity score matching [55]; however, these findings are mainly from studies in Asia but not in studies from Europe or North America [56-58]. As an example, in a population-based cohort study in Korea involving approximately 24,000 patients, patients who received tenofovir had improved outcomes compared with those who received entecavir [55]. In this study, tenofovir was associated with a significantly lower risk of HCC (hazard ratio [HR] 0.61; 95% CI 0.54-0.70) and all-cause mortality or transplant (HR 0.77; 95% CI 0.65-0.92). In contrast, a European study involving 772 patients who received entecavir and 1163 who received tenofovir found that cumulative rates of HCC up to 12 years were not different between the two groups, nor were rates of biochemical or virologic remission, hepatitis B surface antigen (HBsAg) loss, liver transplantation, or death [58]. It is likely that the difference observed in Asian studies is an era effect, because tenofovir was approved almost one decade later than entecavir in Asia compared to a delay of three years in Europe and North America. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Effect on clinical outcomes'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of hepatitis B".)

SUMMARY AND RECOMMENDATIONS

●Use in treatment naïve patients – Entecavir is an orally administered cyclopentyl guanosine analog that is used for the treatment of chronic hepatitis B virus (HBV) infection in adults with evidence of active viral replication and either evidence of active inflammation or advanced fibrosis or cirrhosis. (See 'Introduction' above.)

Monotherapy with entecavir (0.5 mg daily for 52 weeks) in patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic HBV infection was associated with a 5 to 7 log(10) reduction in mean HBV DNA levels. This degree of reduction is greater than what has been observed with adefovir dipivoxil or lamivudine but appears to be similar to that of telbivudine or tenofovir. (See 'HBeAg-positive chronic hepatitis' above and 'HBeAg-negative chronic hepatitis' above.)

●No role for treatment-experienced patients – Entecavir should not be used for treatment of patients with lamivudine resistant HBV since entecavir efficacy is lower and the risk of developing entecavir resistance is greater when compared with those who are lamivudine naïve. Tenofovir is preferred in these patients with lamivudine resistance. (See 'Patients previously treated with lamivudine' above.)

●Risk of developing resistance – Resistance to entecavir is rare (approximately 1 percent after five years treatment) in nucleoside-naïve patients but common (approximately 50 percent after five years treatment) in lamivudine-refractory patients. (See 'Resistance' above.)

●Dosage – For most nucleoside-naïve adults and adolescents older than 16 years of age, the dose of entecavir is 0.5 mg once daily. A higher dose of entecavir (1 mg) should be used for patients with decompensated liver disease. The dose of entecavir should be adjusted in patients with a creatinine clearance of <50 mL/min as described above. (See 'Dose' above.)

●Duration – We determine the optimal duration of therapy for patients with chronic HBV based upon their HBeAg status as well as the presence or absence of cirrhosis. All patients who discontinue treatment with entecavir must be monitored closely for relapse. (See 'Optimal duration of therapy' above and 'Risk of relapse after discontinuing entecavir' above.)