If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Hepatitis B surface antigen quantification at hepatitis B e antigen seroconversion predicts virological relapse after the cessation of entecavir treatment in hepatitis B e antigen-positive patients
Department of Infectious Disease, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215006, Jiangsu Province, ChinaThe Wuxi Fifth Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
Hepatitis B surface antigen (HBsAg) levels at hepatitis B e antigen (HBeAg) seroconversion may be an effective predictor of virological relapse.
•
The variation in HBsAg levels can help guide the timing of cessation of entecavir treatment.
•
Off-treatment virological relapse rates after stopping entecavir treatment were assessed.
Summary
Objectives
To assess off-treatment virological relapse rates and to determine the role of hepatitis B surface antigen (HBsAg) quantification in predicting virological relapse after stopping entecavir (ETV) treatment in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB).
Methods
One hundred and twelve CHB patients for whom ETV was stopped in accordance with the Asian Pacific Association for the Study of the Liver guidelines stopping rules were enrolled. Patient HBsAg and HBV DNA levels were monitored every 4–12 weeks during ETV treatment and after ETV cessation. Post-treatment virological relapse was defined as a serum HBV DNA level of >10 000 copies/ml after stopping ETV treatment.
Results
The virological relapse rate at 52 weeks after stopping ETV was 48.2%. The post-treatment virological relapse rate was significantly higher in patients aged >50 years than in those aged <50 years (p < 0.001), and the virological relapse rate was significantly lower in patients with an HBsAg level <2.0 log10 IU /ml than in those with a level ≥2.0 log10 IU /ml at ETV cessation (p = 0.005). An HBsAg level of 2.5 log10 IU/ml at HBeAg seroconversion was the optimal cut-off value for predicting post-treatment virological relapse (p < 0.001). In those aged <50 years and with HBsAg ≤2.5 log10 IU/ml at HBeAg seroconversion, the relapse rate was only 5%. In patients with HBsAg ≤2.5 log10 IU/ml at HBeAg seroconversion, 52.4% achieved HBsAg levels ≤2.0 log10 IU/ml at ETV cessation, while in those with HBsAg >2.5 log10 IU/ml at HBeAg seroconversion, only 4.4% achieved this criterion.
Conclusions
HBsAg levels can help guide the timing of cessation of ETV treatment. HBsAg levels of 2.5 log10 IU/ml at HBeAg seroconversion may be a useful marker to predict virological relapse after the cessation of ETV treatment in HBeAg-positive CHB patients.
Chronic hepatitis B (CHB) is a major global health problem and a leading cause of liver-related complications, including cirrhosis, liver failure, hepatocellular carcinoma (HCC), and death. The goal of nucleoside/nucleotide analog (NA) therapy for CHB is to suppress the replication of hepatitis B virus (HBV) in a sustained manner, and prevent disease progression to decompensated cirrhosis and HCC.
Comparable efficacy of tenofovir versus entecavir and predictors of response in treatment-naïve patients with chronic hepatitis B: a multicenter real-life study.
However, the durability of off-treatment virological responses has not been fully estimated in patients in whom complete virological suppression is achieved with NA therapy, and relapse rates after stopping NA treatment have not been well established. According to the recommendations of the Asian Pacific Association for the Study of the Liver (APASL),
NA therapy should be stopped in hepatitis B e antigen (HBeAg)-positive CHB patients after HBeAg seroconversion has persisted for more than 12 months. However, some patients develop hepatitis relapse after stopping NA therapy, even when the above recommendation has been followed.
and ETV is used widely in the treatment of CHB patients in China. However, whether or not oral ETV treatment can be discontinued in HBeAg-positive patients, and if so, what the timing of cessation of ETV treatment should be, remain controversial.
Quantitative hepatitis B surface antigen (HBsAg) tests can indirectly reflect the HBV cccDNA level in liver tissue.
On-treatment serum HBsAg level is predictive of sustained off-treatment virologic response to telbivudine in HBeAg-positive chronic hepatitis B patients.
However, reports on the dynamic quantitative monitoring of serum HBsAg levels to predict virological relapse after the cessation of ETV are scarce. The aim of the present study was to analyze the correlation between dynamic serum HBsAg levels and virological relapse in HBeAg-positive patients for whom ETV treatment was stopped in accordance with the APASL guidelines. This study explored the usefulness of HBsAg levels in predicting virological relapse after ETV cessation.
2. Patients and methods
2.1 Patients
Between January 2009 and December 2011, a total of 136 NA-naïve, HBeAg-positive patients attended the Fifth People's Hospital of Wuxi, the First Affiliated Hospital of Soochow University, and the Second Affiliated Hospital of Nanchang University. These patients were selected for the present study if they fulfilled the following criteria: (1) HBsAg positivity for more than 6 months, alanine aminotransferase (ALT) level ≥2 × the upper limit of normal, and HBV DNA level ≥105 copies/ml before ETV treatment; (2) history of ETV treatment for at least 2 years and cessation of ETV treatment when HBeAg seroconversion was maintained for >12 months.
Patients with any of the following were excluded: suspected or imaging/biopsy-confirmed liver cirrhosis before ETV treatment, co-infection with hepatitis A, C, D, and/or E virus, alcoholic liver disease, autoimmune diseases, cholestasis, malignant tumors, severe heart diseases, diabetes, pregnancy, lactation, and history of any NA treatment before ETV or an immune-regulating agent in the past 6 months.
Virological response was defined as HBV DNA being undetectable in serum samples tested using PCR assays (HBV DNA <100 copies/ml). HBeAg seroconversion was defined as HBeAg disappearance and HBeAg antibody appearance. Post-treatment virological relapse was defined as a serum HBV DNA level of >10 000 copies/ml in two consecutive measurements made at least 1 month apart after stopping ETV treatment. Written informed consent was obtained from each subject before and after treatment. The Ethics Committee of the Wuxi Fifth Affiliated Hospital of Jiangnan University approved this study (WXFAH-No.1125).
2.2 Methods
Laboratory assessments were performed at baseline, every 4 weeks before HBeAg seroconversion and every 12 weeks after HBeAg seroconversion during ETV treatment, and every 4–12 weeks after the cessation of ETV treatment. The assessments included tests for the biochemical indicators of liver function, serologic HBV markers (including HBeAg and anti-HBe antibody), and serum HBV DNA and HBsAg quantification. HBV DNA and genotypes were tested with a LightCycler Real-Time II PCR detection system (Roche, Switzerland). The HBV DNA reagent kit was bought from Shanghai Kehua Biotechnology Co. Ltd; this has a sensitivity of 100 copies/ml. HBV genotypes were determined using a commercial real-time PCR kit (Fosun Diagnostics, Shanghai, China). The kit detects HBV genotype with a lower detection limit of 1000 copies/ml. HBV markers were tested using a 1235 Time-Resolved Fluorescent Immunity Analyzer (Perkin-Elmer Life Sciences Company, Finland), and measured with commercially available reagents (Kehua Biotech, Shanghai, China) according to the manufacturer's instructions. The biochemical indicators of liver function were assessed using a Hitachi 7600 fully automatic biochemical analyzer (Hitachi High-tech Company, Japan). Quantitative tests for HBsAg were performed using the i2000 Chemical Luminescent Immuno-analyzer (Abbott, USA) and Abbott reagents, with a diagnostic range from 0.05 IU/ml to 250 IU/ml. When the HBsAg level was >250 IU/ml, a special diluent was used to dilute the sample 100–1000 times, and precise quantitative tests were conducted.
2.3 Statistical analysis
Measurement data were expressed as the mean ± standard deviation. Differences in measurement data were examined using the t-test and analysis of variance. Enumerative data were analyzed using the Chi-square test or Fisher's exact test. Univariate and multivariate analyses were performed using Cox proportional hazards regression models to identify factors associated with virological relapse. Receiver operating characteristic (ROC) curve analysis was used to define the best cut-off point of HBsAg level for predicting virological relapse after ETV cessation. The statistical analysis was performed using SPSS for Windows v. 16.0 software (SPSS Inc., Chicago, IL, USA). A p-value of <0.05 was considered statistically significant.
3. Results
3.1 Baseline characteristics of relapsers and non-relapsers
A total of 136 CHB patients met the selection criteria. Twelve patients with liver cirrhosis and 12 patients who were followed up for less than 24 weeks were excluded. Thus, 112 CHB patients were included in the present study. Of these, 74 were men and 38 were women. The age range of the patients was 22–63 years (mean 40.1 ± 11.2 years). The period of antiviral treatment for these 112 CHB patients was 26–40 months (mean 30.7 ± 3.5 months). The observation period after ETV cessation was 52 weeks. The mean age of the relapsers was 46.1 ± 9.8 years and of non-relapsers was 34.6 ± 9.6 years; the difference in age was statistically significant (p < 0.001). The patients were divided into four subgroups based on their age at ETV commencement: group A, <30 years (n = 32); group B, 30–39 years (n = 30); group C, 40–49 years (n = 24); group D, ≥50 years (n = 36). The respective cumulative rates of post-treatment virological relapse in groups A, B, C, and D were 25.0%, 36.7%, 54.2%, and 84.6%, respectively, at 52 weeks. The virological relapse rate was significantly higher in group D than in groups A, B, and C (all p < 0.001). No significant difference in virological relapse was noted among groups A, B, and C (p = 0.082) (Figure 1).
The baseline HBV DNA levels at ETV commencement in relapsers was 6.8 ± 1.0 log10 copies/ml and in non-relapsers was 6.3 ± 0.8 log10 copies/ml; the difference in HBV DNA levels was statistically significant (p = 0.015) (Figure 2).
Figure 2HBV DNA levels during ETV treatment and after ETV cessation (ETV, entecavir).
The virological relapse rates at ≤12 weeks, 13–24 weeks, 25–36 weeks, and 37–52 weeks were 7.1% (8/112), 24.1% (27/112), 11.7% (13/112), and 5.4% (6/112), respectively. The virological relapse rate at 52 weeks was 48.2% (54/112; Figure 1), and one patient became HBsAg loss during follow-up for 52 weeks. The baseline characteristics of the relapsers and non-relapsers are shown in Table 1.
Table 1Comparison of baseline characteristics between relapsers and non-relapsers
Variables
Total (n = 112)
Relapsers (n = 54)
Non-relapsers (n = 58)
p-Value
Age, years, mean (SD)
40.1 ± 11.2
46.1 ± 9.8
34.6 ± 9.6
<0.001
Sex, male/female, n
74/38
39/15
35/23
0.232
ALT at ETV commencement, IU/l, mean (SD)
195.6 ± 90.1
179.9 ± 87.6
211.2 ± 100.6
0.075
Total bilirubin, mg/dl, mean (SD)
2.2 ± 0.5
2.3 ± 0.3
2.1 ± 0.4
0.761
HBV DNA at ETV commencement (log10 copies/ml), mean (SD)
6.5 ± 1.0
6.8 ± 1.1
6.3 ± 0.7
0.015
HBV genotype, B/C, n
66/46
29/25
37/21
0.338
Baseline HBsAg at ETV commencement (log IU/ml), mean (SD)
3.8 ± 0.7
3.9 ± 0.7
3.7 ± 0.6
0.361
Time of virological response, weeks, mean (SD)
20.6 ± 9.4
22.4 ± 10.0
19.0 ± 8.5
0.06
Course of treatment, months, mean (SD)
30.7 ± 3.5
30.2 ± 3.8
31.2 ± 3.1
0.112
SD, standard deviation; ALT, alanine aminotransferase; ETV, entecavir; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen.
3.2 Correlation between baseline HBsAg level at ETV commencement and HBV relapse after stopping ETV treatment
The baseline HBsAg levels at the commencement of ETV treatment did not differ significantly between the relapsers and non-relapsers (p = 0.361; Table 1). In patients with a baseline HBsAg level ≤3.0 log10 IU/ml and HBV DNA level ≤6.0 log10 copies/ml at ETV commencement, the HBV relapse rate at 52 weeks after stopping the ETV treatment was 15.8% (3/19). In contrast, in those with baseline HBsAg >3.0 log10 IU/ml and/or HBV DNA >6.0 log10 copies/ml, the virological relapse rate was 54.8% (51/93). The difference was statistically significant (p = 0.002).
3.3 Correlation between HBsAg levels at 12 weeks of ETV treatment and HBV relapse after ETV discontinuation
The HBsAg levels at 12 weeks of ETV treatment did not significantly differ between the relapsers and non-relapsers (p = 0.252; Figure 3). However, in patients in whom the HBsAg level had declined by ≥1.0 log10 IU/ml at 12 weeks of treatment, the virological relapse rate was 7.7% (1/13), whereas this rate was 53.5% (53/99) in those whose HBsAg level at 12 weeks had declined by <1.0 log10 IU/ml. The difference in relapse rates was statistically significant (p = 0.002).
Figure 3HBsAg levels at different time-points during ETV treatment (HBsAg, hepatitis B surface antigen; ETV, entecavir).
3.4 Correlation between HBsAg level at HBeAg seroconversion and HBV relapse after ETV cessation
The HBsAg level at the time of HBeAg seroconversion in virological relapsers was 3.75 ± 0.57 log10 IU/ml and in non-relapsers was 3.12 ± 0.72 log10 IU/ml (p < 0.001). A ROC curve of the HBsAg levels in the 112 patients at the time of HBeAg seroconversion was plotted. The area under the ROC curve was 0.751 (95% confidence interval (CI) 0.660–0.842, p < 0.001; Figure 4). The optimal cut-off value of HBsAg level at HBeAg seroconversion was 2.72 log10 IU/ml. An HBsAg level of 2.5 log10 IU/ml was used as a marker for predicting virological relapse. In patients with HBsAg levels ≤2.5 and >2.5 log10 IU/ml at the time of at HBeAg seroconversion, the virological relapse rates were 9.5% (2/21) and 57.1% (52/91), respectively (Chi-square = 15.496, p < 0.001).
Figure 4Area under the receiver operating characteristic curve of HBsAg at different time-points (HBsAg, hepatitis B surface antigen; ETV, entecavir).
Because age and HBsAg level at HBeAg seroconversion were independent predictors of virological relapse, the patients were divided into three subgroups based on their age (<50 and ≥50 years) and HBsAg level at HBeAg seroconversion (≤2.5 log10 IU/ml and >2.5 log10 IU/ml) as follows: group E with age <50 years and HBsAg level ≤2.5 log10 IU/ml, group F with age <50 years and HBsAg level >2.5 log10 IU/ml, and group G with age ≥50 years and regardless of their HBsAg level; the virological relapse rates in groups E, F, and G were 6.7% (1/15), 43.7% (31/71), and 84.6% (22/26), respectively. The virological relapse rate was significantly higher in group G than in groups E and F (all p < 0.001) and higher in group F than in group E (p = 0.007).
3.5 Correlation between HBsAg levels at ETV cessation and HBV relapse after ETV cessation
The HBsAg levels at ETV cessation differed significantly between the relapsers and non-relapsers (3.58 ± 0.54 log10 IU/ml vs. 2.99 ± 0.64 log10 IU/ml, t = − 2.866, p = 0.005; Figure 5). The area under the ROC curve of the HBsAg levels at ETV cessation in the 112 patients was 0.671 (95% CI 0.572–0.770, p = 0.002; Figure 4) and could be used to predict virological relapse. The optimal cut-off value of HBsAg level at ETV cessation to predict virological relapse was 2.24 log10 IU/ml. In patients whose HBsAg levels at ETV cessation were ≤2.0 log10 and >2.0 log10 IU/ml, the virological relapse rates were 13.3% (2/15) and 53.6% (52/97), respectively (p = 0.005). In patients whose HBsAg was ≤2.5 log10 IU/ml at HBeAg seroconversion, 52.4% achieved HBsAg levels ≤2.0 log10 IU/ml at ETV cessation, while in patients whose HBsAg was >2.5 log10 IU/ml at HBeAg seroconversion, only 4.4% achieved this criterion.
3.6 Correlation between HBsAg level at 12 weeks after ETV cessation and HBV relapse after ETV cessation
The virological relapse rate at 52 weeks after the cessation of ETV treatment was 81.3% (26/32) in patients whose HBsAg levels increased by ≥1.0 log10 IU/ml at 12 weeks after ETV cessation. The relapse rate was 48.7% (19/39) in patients whose HBsAg levels increased by <1.0 log10 IU/ml at 12 weeks after ETV cessation. The relapse rate was 22.0% (9/41) in patients whose HBsAg levels did not increase or decreased at 12 weeks after the cessation of ETV treatment. There was a significant difference among these three groups (p < 0.001).
3.7 Multivariate Cox model analysis
A univariate analysis of age, sex, genotypes, baseline ALT, baseline HBV DNA, baseline HBsAg level at ETV commencement, virological response time (weeks), HBsAg level at HBeAg seroconversion, and HBsAg level at ETV cessation was first conducted. The factors that showed statistically significant results were then selected for multivariate Cox model analysis, namely age, baseline HBV DNA, HBsAg level at HBeAg seroconversion, and HBsAg level at ETV cessation. Factors that significantly affected virological relapse rates after ETV cessation were age (p = 0.001), HBsAg level at HBeAg seroconversion (p = 0.002), and HBsAg level at ETV cessation (p = 0.037), in that order (Table 2).
Table 2Factors predictive of post-treatment HBV relapse for 112 patients
Factors
Univariate analysis
Multivariate analysis
HR
95% CI
p-Value
HR
95% CI
p-Value
Age
1.054
1.031–1.077
<0.001
1.040
1.016–1.065
0.001
Sex
0.738
0.407–1.339
0.318
ALT at ETV commencement
0.997
0.994–1.001
0.128
HBV DNA at ETV commencement
1.291
1.010–1.649
0.042
1.164
0.919–1.475
0.208
HBV genotype
1.442
0.844–2.464
0.180
Virological response time
1.024
0.997–1.052
0.079
HBsAg at ETV commencement
1.103
0.733–1.661
0.638
HBsAg level at HBeAg seroconversion
2.743
1.784–4.219
<0.001
2.162
1.338–3.493
0.002
HBsAg level at ETV cessation
2.356
1.494–3.716
<0.001
1.679
1.032–2.733
0.037
HBV, hepatitis B virus; HR, hazard ratio; CI, confidence interval; ALT, alanine aminotransferase; ETV, entecavir; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen.
Previous studies in European and American subjects have indicated that the maintenance rate of virological response after the cessation of NA therapy reaches 80–90%; however, this rate in Asian patients is only about 50%.
Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
and Ridruejo et al. reported a 26% virological relapse rate in HBeAg-positive patients at a median of 48 weeks after the discontinuation of ETV treatment.
This study also showed a similar high virological relapse rate (48.2%) in HBeAg-positive patients at 52 weeks after ETV cessation. Most of the patients relapsed at 12–36 week after ETV cessation; the virological relapse rate in patients whose HBsAg level had increased ≥1.0 log10 IU/ml at 12 weeks after ETV cessation was much higher (81.3%) than that of patients whose HBsAg level increased slowly or remained decreased. Therefore, it is necessary to monitor HBV DNA levels and HBsAg levels closely after ETV cessation to predict and detect virological relapse in a timely manner (Figure 5).
Figure 5HBsAg levels at different time-points after ETV cessation (HBsAg, hepatitis B surface antigen; ETV, entecavir).
Recent studies have found that quantitative tests for serum HBsAg levels and HBV DNA and dynamic monitoring of these levels can predict the effects of antiviral treatment with peginterferon alfa-2a and the relapse of hepatitis after medication cessation.
Chen et al. reported that a higher baseline HBsAg level at ETV commencement was an independent predictor of clinical relapse and that the baseline HBV DNA level was not associated with clinical relapse in HBeAg-positive CHB patients.
Seto et al. reported that baseline and subsequent serial HBsAg levels had no association with virological relapse in HBeAg-negative CHB patients. The authors explained this as the decoupling of serum HBsAg and HBV DNA production in HBeAg-negative disease.
In the HBeAg-positive CHB patients in the present study, it was also found that the baseline HBsAg level at ETV commencement was not an independent predictor of virological relapse. Baseline HBV DNA levels at ETV commencement were significantly higher in relapsers than in non-relapsers, but multivariate Cox model analysis showed baseline HBV DNA not to be an independent risk factor; the reason for this is the large overlap in HBV DNA levels in relapsers and non-relapsers. However, the present data show that patients who had low baseline HBsAg levels ≤3.0 log10 IU/ml and baseline HBV DNA levels ≤6.0 log10 copies/ml at ETV commencement had low relapse rates after ETV cessation (15.8%, 3/19). This may be useful for physician reference.
Chan et al. reported that the reduction in HBsAg levels from baseline to the end of treatment could predict post-lamivudine virological relapse rates.
Wursthorn et al. reported that a rapid decrease in HBsAg level after oral telbivudine treatment for 24 weeks could achieve a high rate of HBeAg seroconversion and that long-term treatment could eliminate HBsAg, which could be used to predict the relapse of hepatitis after drug cessation.
Data from the present study also show that a rapid decrease in HBsAg (HBsAg level decrease ≥1.0 log10 IU/ml) after 12 weeks of ETV treatment could result in a low virological relapse rate (7.7%, 1/13).
In this study, it was found that age and HBsAg level at HBeAg seroconversion were independent predictors of virological relapse. Based on subgroup data combining age and HBsAg level at HBeAg seroconversion, it is recommended that patients aged ≥50 years should not stop therapy regardless of their HBsAg level because their relapse rate was 84.6% (22/26). Patients aged <50 years and with an HBsAg level ≤2.5 log10 IU/ml at HBeAg seroconversion may stop ETV therapy based on the APASL recommended stopping rules, because their relapse rate was only 6.7% (1/15). Patients aged <50 years and with an HBsAg level >2.5 log10 IU/ml at HBeAg seroconversion still showed a high relapse rate (43.7%, 31/71). Furthermore, it was found that only a few patients (4.4%, 4/91) could achieve HBsAg levels <2.0 log10 IU/ml under the current APASL recommended consolidation time. Thus it is recommended that these patients should undergo regular monitoring of their HBsAg levels and should stop ETV therapy only when their HBsAg level is <2.0 log10 IU/ml.
Liang et al. reported that the HBsAg level at the end of treatment was related to a low relapse rate; only 9% of patients with HBsAg levels ≤2.0 log10 IU/ml had a virological relapse.
The present study showed the relapse rate to be 13.3% (2/15) when the HBsAg levels were <2.0 log10 IU/ml at ETV cessation, which is consistent with the previous study. This phenomenon should be investigated further because it might be that an HBsAg level <2.5 log10 IU/ml at HBeAg seroconversion will be a more useful marker and earlier index than an HBsAg level <2.0 log10 IU/ml at ETV cessation to guide and predict the timing of stopping ETV therapy.
This study has a few limitations. First, this was a retrospective study and therefore a selection bias is possible. Second, the HBsAg level at HBeAg seroconversion was difficult to determine precisely in terms of the exact time of HBeAg seroconversion, because these seromarkers were monitored at regular intervals of 4 weeks or even longer. Third, this study did not determine whether a different duration of prolonged consolidation therapy would influence the relapse rate, and the follow-up period after ETV cessation was only 52 weeks; this is too short to observe the long-term relapse rate. Finally, HBeAg seroconverters under ETV therapy are only a minority, and cessation of therapy is not a useful option for the majority of patients.
In conclusion, the virological relapse rate at 52 weeks after stopping ETV was 48.2%. The variation in HBsAg levels during ETV treatment and after ETV cessation could help guide the timing of cessation of ETV treatment. A serum HBsAg level ≤2.5 log10 IU/ml at the time of HBeAg seroconversion may be a useful marker to predict virological relapse after the cessation of ETV treatment in HBeAg-positive CHB patients.
Acknowledgements
We thank Professor Jiming Zhang (Department of Infections, Huashan Hospital, affiliated to Fudan University) for his helpful advice and for help on this research work.
Funding: This study was supported by the Chinese Foundation for Hepatitis Prevention and Control – TianQing Liver Disease Research (grant No. TQGB2011004), Nanjing Medical University of Science and Technology (grant No. 2012NJMU072), and Wuxi Technology Development Fund (grant No. 2013CSE31N1318).
Conflict of interest: The authors of this study declare that they do not have anything to disclose regarding funding or conflicts of interest with respect to this manuscript.
References
European Association for the Study of the Liver
EASL clinical practice guidelines: management of chronic hepatitis B virus infection.
Comparable efficacy of tenofovir versus entecavir and predictors of response in treatment-naïve patients with chronic hepatitis B: a multicenter real-life study.
On-treatment serum HBsAg level is predictive of sustained off-treatment virologic response to telbivudine in HBeAg-positive chronic hepatitis B patients.
Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.
00253-2&id=gr1.jpg){kind=link}
00253-2&id=gr2.jpg){kind=link}
00253-2&id=gr3.jpg){kind=link}
00253-2&id=gr4.jpg){kind=link}
00253-2&id=gr5.jpg){kind=link}