OBJECTIVE: To investigate the value of HBV RNA for predicting the therapeutic effect of long-term entecavir (ETV) antiviral therapy in patients with chronic hepatitis B (CHB). METHODS: Serum samples were collected from 59 CHB patients treated with ETV for 96 or 108 months. HBV RNA levels, HBV DNA levels, and serological marker (HBeAg) levels were measured at baseline and 3, 6, 9, 12, 36, 72, and 96 (or 108) months during the therapy. RESULTS: Although HBV RNA level decreased after 12 and 36 months of ETV antiviral therapy, no significance changes occurred in HBV RNA negative conversion rate (P>0.05). After 72 months of treatment or longer, 33 patients had HBV RNA levels lower than 100 copies/mL, and among them 29 patients had HBV RNA levels lower than the detection limit, and HBV RNA negative conversion rate was statistically significant (P < 0.05). A lower HBV RNA level was associated with a higher HBeAg negative conversion rate (P < 0.05). Age and HBV RNA level were positively correlated with HBeAg negative conversion rate (P < 0.05). CONCLUSION Prolonged ETV antiviral therapy results in better clearance of HBV RNA and a higher negative conversion rate in CHB patients. The length of antiviral therapy and age are positively correlated with the negative conversion rate of HBV RNA, and earlier administration of the antiviral treatment achieves better therapeutic effect. Serum HBV RNA level can be used as an indicator for predicting conversion to negative HBeAg in CHB patients receiving ETV therapy.
Antiviral Agents/therapeutic use* ; DNA, Viral ; Guanine/analogs & derivatives* ; Hepatitis B e Antigens ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic ; Humans ; RNA

Objective: To explore the efficacy of entecavir antiviral therapy on the degree of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) combined with chronic hepatitis B (CHB) in Tibet region. Methods: HBeAg-positive CHB patients who were treated with entecavir in the outpatient and inpatient Department of Infectious Diseases of the Tibet Autonomous Region people's Hospital between January 2018 to December 2019 were retrospectively analyzed. Among the 140 subjects with CHB, 95 cases were CHB alone, and the other 45 cases were diagnosed as CHB combined with NAFLD by ultrasound. All patients were given entecavir 0.5 mg orally once daily on an empty stomach for 48 weeks. HBeAg negative conversion rate, blood glucose, blood lipid, liver function and the degree of liver fibrosis were compared between the two groups at the 12th, 24th and 48th weeks of treatment to evaluate the virological response. SPSS 19.0 statistical software was used to process the data. Measurement data were expressed as mean ± standard deviation (x¯±s). Descriptive statistical analysis was used for t-test, and the categorical variables were expressed as percentage (%) and χ² test. A p-value < 0.05 was considered as statistically significant. Results: After 48 weeks of treatment, the HBeAg and HBV DNA negative conversion rate were significantly better in patients with CHB alone (group B) than CHB combined with NAFLD (group A), that is to say, HBeAg negative conversion rate in group A and B patients were 28.90% and 40%, respectively, and group B was better than group A. HBV DNA negative conversion rate was significantly elevated in group B (83.2%) than group A (64.4%), with statistical significance (P<0.05), and the difference between the both groups was statistically significant. Alanine aminotransferase level was significantly decreased in patients with CHB alone than patients with CHB combined with NAFLD. Aspartate aminotransferase/platelet ratio index was significantly decreased after treatment than before treatment in both group of patients, and the depletion was more pronounced in CHB alone group. Liver stiffness values were significantly decreased in patients with CHB combined with NAFLD than CHB alone group. Moreover, liver stiffness values was higher in group A than group B before treatment under the influence of fat attenuation factors, and the differences before treatment and after treatment were 3.50±4.66 and 2.05±2.53, respectively; however, group B was not affected by fat attenuation factors, so LSM value reduction in group A was more obvious, and the differences were statistically significant. There was no statistically significant difference in blood glucose and blood lipids levels before and after treatment between the two groups. Conclusion: NAFLD has a certain effect on antiviral therapy and liver fibrosis in patients with CHB, i.e., the effect of antiviral therapy in patients with CHB alone is better than patients with CHB combined with NAFLD. Patients with CHB combined with NAFLD when treated with antiviral therapy had a significantly greater degree of liver stiffness reduction than patients with CHB alone. Therefore, it is necessary to actively intervene the risk factors associated with NAFLD according to the actual situation of different individuals to improve clinical efficacy of antiviral therapy.
Antiviral Agents/therapeutic use* ; DNA, Viral ; Guanine/analogs & derivatives* ; Hepatitis B e Antigens ; Hepatitis B, Chronic/drug therapy* ; Humans ; Liver Cirrhosis/complications* ; Non-alcoholic Fatty Liver Disease/drug therapy* ; Retrospective Studies ; Tibet ; Treatment Outcome

Objective: To dynamically observe the clinical efficacy of entecavir and the changes of PD-1⁺CXCR5⁺CD4⁺T lymphocytes and sPD-1 levels in peripheral blood of HBeAg-positive chronic hepatitis B virus carriers treated with entecavir, and further explore its clinical significance. Methods: There were 31 cases of chronic hepatitis B virus carriers in the treatment group (A), 32 cases of chronic hepatitis B virus carriers in the treatment group (B), and 15 cases of chronic hepatitis B virus carriers in the non-treatment group (C).Three groups peripheral blood samples and clinical data at 0, 24 and 48 weeks were collected and compared. PD-1⁺CXCR5⁺CD4⁺T lymphocytes were detected by flow cytometry, and the level of sPD-1 was detected by enzyme-linked immunosorbent assay. ANOVA and Spearman correlation analysis were performed on the measurement data among the three groups. Results: At week 0, the serum levels of HBsAg, HBeAg and HBV DNA were significantly higher in groups A and C than group B. PD-1⁺CXCR5⁺CD4⁺T lymphocytes in peripheral blood were significantly higher in group B (4.70%±1.58%) than group A (3.25%±1.01%) and group C (2.77%±0.67%) (F=16.65, P<0.05). There was no significant difference between group A and group C (P>0.05). Peripheral blood sPD-1 in group B [(1 866.62±1 472.70) pg/ml] was significantly higher than group A [(824.86±538.66) pg/ml] and group C [(618.19±602.62) pg/ml] (F=10.95, P<0.05). There was no significant difference between group A and group C (P>0.05). At 48 weeks, the serum HBsAg did not decrease significantly in groups A and C than baseline (P>0.05), but were significantly higher than group B (P<0.05). Serum HBeAg levels were decreased significantly in groups A and B than baseline (P<0.05). <0.05), but group A was significantly higher than group B (P<0.05), and there was no significant difference between group A and group C (P>0.05). Serum HBV DNA level was significantly lower in groups A and B than group C (P<0.05), and there was no significant difference between group A and group B (P>0.05). Peripheral blood PD-1⁺CXCR5⁺CD4⁺T lymphocytes were significantly lower in Group A (1.56%±0.73%) and group B (1.32%±0.43%) than group C (2.64%±0.85%) (P<0.05). Peripheral blood sPD-1 were significantly lower in group A [(289.05±215.86) pg/ml] and group B [(236.01±173.92) pg/ml] than group C [(650.34±598.46) pg/ml] (P<0.05). There was no significant difference between group A and group B. Correlation analysis results: In group A at 48 weeks, the decreased level of PD-1⁺CXCR5⁺CD4⁺T lymphocyte ratio had no correlation with the decreased level of HBsAg and HBV DNA, but was positively correlated with the decreased level of HBeAg (r=0.376, P<0.05). The decreased level of sPD-1 had no correlation with the changes of HBsAg, but was positively correlated with the decreased levels of HBeAg and HBV DNA (r=0.598 and 0.384, P<0.05). In group B at 48 weeks, the decreased levels of PD-1⁺CXCR5⁺CD4⁺T lymphocytes and sPD-1 were positively correlated with the decreased levels of HBsAg, HBeAg, and HBV DNA (P<0.05). Conclusion: Hepatitis B virus replication and expressions in HBeAg-positive chronic hepatitis B virus carriers were significantly inhibited after 48 weeks of antiviral treatment, which is related not only to entecavir treatment, but also to the immunological mechanism involved in sPD-1. Moreover, the inhibition of HBeAg expression is associated with a decrease in the number and/or activity of PD-1⁺CXCR5⁺CD4⁺T lymphocytes.
Antiviral Agents/therapeutic use* ; DNA, Viral ; Guanine/analogs & derivatives* ; Hepatitis B Surface Antigens ; Hepatitis B e Antigens ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic ; Humans ; Programmed Cell Death 1 Receptor ; Receptors, CXCR5/analysis* ; T-Lymphocytes

OBJECTIVES: Hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) is the most common type of liver failure in China, with a high mortality. Early rapid reduction of HBV-DNA load can improve the survival rate of HBV-ACLF patients. At present, the commonly used drugs are nucleoside (acid) analogues, such as entecavir (ETV), tenofovir, and so on. The newly listed tenofovir alafenamide fumarate (TAF) has attracted great attention of clinicians because of its stronger antiviral effect, higher transaminase normalization rate, better bone and kidney safety, and zero drug resistance. However, there are few clinical research data on the efficacy and safety of TAF in the treatment of Chinese HBV-ACLF patients, and there is a lack of pharmacoeconomic evaluation. This study aims to compare the efficacy, safety, and cost-effectiveness between TAF and ETV in patients with HBV-ACLF. METHODS: The data were collected from 196 HBV-ACLF patients (80 patients in the TAF group and 116 patients in the ETV group) who were hospitalized in Xiangya Hospital, Central South University from May 2020 to March 2021. Biochemistry and virology were detected before and after treatment (at baseline, Week 2, 4, and 12). Clinical features, disease prognosis, and cost-effectiveness were compared between the 2 groups. According to the baseline, HBV-ACLF patients were divided into 4 stages including pre-liver failure stage, early stage, medium stage, and end stage. And the liver transplantation rate and mortality was also compared. Pharmacoeconomic evaluation was taken using cost-effectiveness analysis and cost minimization analysis．. RESULTS: After 4 weeks of treatment, there were no significant differences in the efficacy (liver function, viral load) between the 2 groups (all P>0.05). The TAF group showed lower creatinine [(80.35±18.77) μmol/L vs (105.59±82.32) μmol/L, P<0.05] and higher estimated glomerular filtration rate (eGFR) levels [(95.65±23.21) mL/(min·1.73 m²) vs (82.68±26.32) mL/(min·1.73 m²), P<0.05] than the ETV group. After 12 weeks of treatment, the analysis of overall the liver transplantation rate and mortality between the 2 groups showed similar conclusion. However, the TAF group had a lower the liver transplantation rate and mortality than the ETV group in patients with pre-liver failure (0vs13.89%, P<0.05). No evident distinction was found in the liver transplantation rate and mortality during the early, medium, or end stages of liver failure (13.04% vs 17.65%, 37.50% vs 37.04%, and 54.55% vs 68.42%, respectively). Ratio of cost to effectiveness in the ETV group was higher than that in the TAF group. CONCLUSIONS TAF is not more efficient than ETV group in improving liver function and reducing viral load for HBV-ACLF patients and they also show similar safety. However, TAF has a greater advantage over ETV not only in preserving renal function, but also in reducing the liver transplantation rate and mortality in patients with pre-liver failure. TAF can provide economic benefit to patients with HBV-ACLF.
Acute-On-Chronic Liver Failure/drug therapy* ; Alanine/therapeutic use* ; Antiviral Agents/therapeutic use* ; Guanine/analogs & derivatives* ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/drug therapy* ; Humans ; Tenofovir/analogs & derivatives* ; Treatment Outcome

BACKGROUND: Hepatectomy for hepatocellular carcinoma (HCC) beyond the Milan criteria is shown to be beneficial. However, a high rate of post-operative HCC recurrence hinders the long-term survival of the patients. This study aimed to investigate and compare the impacts of tenofovir (TDF) and entecavir (ETV) on the recurrence of hepatitis B viral (HBV)-related HCC beyond the Milan criteria. METHODS: Data pertaining to 1532 patients who underwent hepatectomy and received antiviral therapy between January 2014 and January 2019 were collected from five centers. Recurrence-free survival (RFS) analysis was performed using the Kaplan-Meier method. Cox proportional hazards regression analysis was performed to determine prognostic factors for HCC recurrence. RESULTS: The analysis incorporates 595 HBV-related HCC patients. The overall 5-year RFS was 21.3%. Among them, 533 and 62 patients received ETV and TDF treatment, respectively. The 1-, 3-, and 5-year RFS rates were 46.3%, 27.4%, and 19.6%, respectively, in the ETV group compared with 65.1%, 41.8%, and 37.2%, respectively, in the TDF group (P < 0.001). Multivariate analysis showed that TDF treatment (hazard ratio [HR]: 0.604, P = 0.005), cirrhosis (HR: 1.557, P = 0.004), tumor size (HR: 1.037, P = 0.008), microvascular invasion (MVI) (HR: 1.403, P = 0.002), portal vein tumor thrombus (PVTT) (HR: 1.358, P = 0.012), capsular invasion (HR: 1.228, P = 0.040), and creatinine levels (CREA) (HR: 0.993, P = 0.031) were statistically significant prognostic factors associated with RFS. CONCLUSIONS Patients with HCC beyond the Milan criteria exhibited a high rate of HCC recurrence after hepatectomy. Compared to the ETV therapy, TDF administration significantly lowered the risk of HCC recurrence.
Antiviral Agents/therapeutic use* ; Carcinoma, Hepatocellular/surgery* ; Guanine/analogs & derivatives* ; Hepatectomy ; Hepatitis B virus ; Hepatitis B, Chronic/drug therapy* ; Humans ; Liver Neoplasms/surgery* ; Retrospective Studies ; Tenofovir/therapeutic use*

OBJECTIVE: To evaluate the therapeutic effects of entecavir (ETV) and interferon- (IFN-) treatments for 48 weeks for chronic hepatitis B (CHB) in patients with different baseline alanine aminotransferase (ALT) levels. METHODS: We retrospectively analyzed the data of 369 CHB patients receiving ETV and IFN- treatments for 48 weeks. We compared the virological response rates, HBsAg clearance, and HBsAg reduction between the patients receiving ETV and IFN- treatments with different baseline ALT levels[≤ 5×upper limits of normal (ULN) level (subgroup 1), 5-10×ULN (subgroup 2), and > 10× ULN (subgroup 3)]. RESULTS: In patients receiving ETV treatment, the virological response rate was 83.3% in subgroup 1, 91.4% in subgroup 2, and 95.5% in subgroup 3, as compared with 19.7%, 40%, and 42.9% in the 3 subgroups with IFN- treatment, respectively, showing significantly differences both among different subgroups with the same treatment and between the same subgroup with different treatments ( < 0.05). HBeAg clearance rates in the 3 subgroups were 8.3%, 16.7% and 35.5% in patients with ETV treatment and were 1.8%, 41.9%, and 38.1% in patients with IFN- treatment, respectively, showing significant differences among the 3 subgroups with the same treatment ( < 0.05); in the same subgroups with different treatments, the rates differed significantly only between subgroups 2 ( < 0.05). In ETV group, the rate of HBsAg reduction to below 200 IU/ml was 2.5% in subgroup 1 and 13.8% in subgroup 2, showing no significant difference between the two subgroups; in IFN- group, the rates were also similar between subgroups 1 and 2 (30.6% 33.3%, > 0.05); but the rates differed significantly between the same subgroups with different treatments ( < 0.05). CONCLUSIONS In all the subgroups with different baseline ALT levels, ETV treatment for 48 weeks results in significantly higher virological response rates than IFN- treatment in patients with CHB. In patients with a baseline ALT of 5-10 ×ULN, IFN- can result in a higher HBeAg clearance rate than ETV. In patients with comparable baseline ALT level, IFN- more effectively reduces HBsAg level than ETV. The patients with a relatively high baseline ALT level (> 5 × ULN) show better responses to both ETV and IFN- treatment than those with ALT level below 5×ULN. We thus recommend IFN- for patients with a baseline ALT of 5-10×ULN and ETV for patients with a baseline ALT either below 5 × ULN or beyond 10×ULN.
Alanine Transaminase ; blood ; Antiviral Agents ; therapeutic use ; DNA, Viral ; Guanine ; analogs & derivatives ; therapeutic use ; Hepatitis B Surface Antigens ; blood ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; immunology ; Hepatitis B, Chronic ; drug therapy ; enzymology ; immunology ; virology ; Humans ; Interferon-alpha ; therapeutic use ; Retrospective Studies ; Time Factors ; Treatment Outcome ; Viral Load ; drug effects

OBJECTIVETo evaluate the effect of long-term therapy with entecavir and Fufang Biejia Ruangan tablet in patients with chronic hepatitis B (CHB)-associated fibrosis and explore the synergistic therapy that accelerates the reversion of liver fibrosis.

METHODSA total of 197 patients with CHB-associated fibrosis were recruited from Nanfang Hospital between June, 2010 and June, 2015. The patients were divided into two groups after matching for age, gender and liver stiffness measurement (LSM), namely group A (n=98) treated with Fufang Biejia Ruangan Tablet plus entecavir, and group B (n=99) to receive entecavir only. HBV DNA quantification, HBV serological indicators, blood biochemical indexes, and results of abdominal ultrasound and FibroScan were recorded every 12 weeks. FibroScan values were converted to Metavir staging.

RESULTSBoth groups showed significant decreases in serum levels of HBV DNA, alanine aminotransferase (ALT), and LSM value from baseline (all P<0.05). The median time to achieve Metavir fibrosis staging improvement were 72 weeks in group A and 96 weeks in group B (P<0.05), and the median time to achieve ALT and AST normalization were 12 and 24 weeks in Group A, respectively, significantly shorter than the time in group B (P<0.05). No significant difference was found between the two groups in HBV DNA undetectable rate and HBeAg seroconversion rate.

CONCLUSIONThe combination therapy with Fufang Biejia Ruangan tablet and entecavir produces a stronger efficacy than entecavir alone in the treatment of chronic hepatitis B patients with liver fibrosis, and Fufang Biejia Ruangan tablet shows an obvious hepatoprotective effect in these patients.

Alanine Transaminase ; blood ; DNA, Viral ; blood ; Drugs, Chinese Herbal ; therapeutic use ; Guanine ; analogs & derivatives ; therapeutic use ; Hepatitis B e Antigens ; blood ; Hepatitis B, Chronic ; drug therapy ; Humans ; Liver Cirrhosis ; drug therapy ; Tablets

BACKGROUND/AIMS: Clear indicators for stopping antiviral therapy in chronic hepatitis B (CHB) patients are not yet available. Since the level of hepatitis B surface antigen (HBsAg) is correlated with covalently closed circular DNA, the HBsAg titer might be a good indicator of the off-treatment response. This study aimed to determine the relationship between the HBsAg titer and the entecavir (ETV) off-treatment response. METHODS: This study analyzed 44 consecutive CHB patients (age, 44.6±11.4 years, mean±SD; men, 63.6%; positive hepatitis B envelope antigen (HBeAg) at baseline, 56.8%; HBV DNA level, 6.8±1.3 log₁₀ IU/mL) treated with ETV for a sufficient duration and in whom treatment was discontinued after HBsAg levels were measured. A virological relapse was defined as an increase in serum HBV DNA level of >2000 IU/mL, and a clinical relapse was defined as a virological relapse with a biochemical flare, defined as an increase in the serum alanine aminotransferase level of >2 × upper limit of normal. RESULTS: After stopping ETV, virological relapse and clinical relapse were observed in 32 and 24 patients, respectively, during 20.8±19.9 months of follow-up. The cumulative incidence rates of virological relapse were 36.2% and 66.2%, respectively, at 6 and 12 months, and those of clinical relapse were 14.3% and 42.3%. The off-treatment HBsAg level was an independent factor associated with clinical relapse (hazard ratio, 2.251; 95% confidence interval, 1.076–4.706; P=0.031). When patients were grouped according to off-treatment HBsAg levels, clinical relapse did not occur in patients with an off-treatment HBsAg level of ≤2 log10 IU/mL (n=5), while the incidence rates of clinical relapse at 12 months after off-treatment were 28.4% and 55.7% in patients with off-treatment HBsAg levels of >2 and ≤3 log₁₀ IU/mL (n=11) and >3 log₁₀ IU/mL (n=28), respectively. CONCLUSION: The off-treatment HBsAg level is closely related to clinical relapse after treatment cessation. A serum HBsAg level of <2 log₁₀ IU/mL is an excellent predictor of a sustained off-treatment response in CHB patients who have received ETV for a sufficient duration.
Adult ; Alanine Transaminase/blood ; Antiviral Agents/*therapeutic use ; DNA, Viral/blood ; Female ; Follow-Up Studies ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B Surface Antigens/blood ; Hepatitis B virus/genetics/isolation & purification ; Hepatitis B, Chronic/*drug therapy ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Polymerase Chain Reaction ; Recurrence ; Treatment Outcome

BACKGROUND/AIMS: Before tenofovir (TDF) become available in South Korea, combination therapy with entecavir (ETV) and adefovir (ADV) was the most potent regimen for chronic hepatitis B (CHB) patients who fail to respond to rescue therapy for drug resistance. We analyzed the efficacy of ETV-ADV combination therapy and investigated the clinical and clonal results of TDF-based rescue therapy in CHB patients refractory to this combination. METHODS: We retrospectively reviewed the medical records of CHB patients treated for up to 3 years with ETV-ADV combination therapy as a rescue therapy for drug resistance. In cases refractory to this combination, clinical and clonal analyses were performed for TDF-based rescue therapy. RESULTS: The analysis was performed on 48 patients. Twelve patients achieved a virological response (VR) within 3 years. A VR was subsequently achieved in nine of the ten patients without a VR who switched to TDF monotherapy. A VR was also achieved in six of the seven patients who switched to lamivudine-TDF combination therapy, and in two of the two patients who switched to ETV-TDF combination therapy. In an in vitro susceptibility test, viral replication was detected with TDF monotherapy but not with ETV-TDF combination therapy. CONCLUSIONS: The efficacy of ETV-ADV combination therapy was insufficient in CHB patients who were refractory to rescue therapy. A more potent regimen such as ETV-TDF combination therapy may be considered in such refractory cases.
Adenine/*analogs & derivatives/therapeutic use ; Adult ; Aged ; Antiviral Agents/*therapeutic use ; DNA, Viral/analysis/metabolism ; Drug Resistance, Viral ; Drug Therapy, Combination ; Female ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B virus/genetics/isolation & purification ; Hepatitis B, Chronic/*drug therapy/virology ; Humans ; Male ; Middle Aged ; Organophosphonates/*therapeutic use ; Polymerase Chain Reaction ; Republic of Korea ; Retrospective Studies ; Tenofovir/*therapeutic use ; Treatment Outcome

BACKGROUND/AIMS: Before tenofovir (TDF) become available in South Korea, combination therapy with entecavir (ETV) and adefovir (ADV) was the most potent regimen for chronic hepatitis B (CHB) patients who fail to respond to rescue therapy for drug resistance. We analyzed the efficacy of ETV-ADV combination therapy and investigated the clinical and clonal results of TDF-based rescue therapy in CHB patients refractory to this combination. METHODS: We retrospectively reviewed the medical records of CHB patients treated for up to 3 years with ETV-ADV combination therapy as a rescue therapy for drug resistance. In cases refractory to this combination, clinical and clonal analyses were performed for TDF-based rescue therapy. RESULTS: The analysis was performed on 48 patients. Twelve patients achieved a virological response (VR) within 3 years. A VR was subsequently achieved in nine of the ten patients without a VR who switched to TDF monotherapy. A VR was also achieved in six of the seven patients who switched to lamivudine-TDF combination therapy, and in two of the two patients who switched to ETV-TDF combination therapy. In an in vitro susceptibility test, viral replication was detected with TDF monotherapy but not with ETV-TDF combination therapy. CONCLUSIONS: The efficacy of ETV-ADV combination therapy was insufficient in CHB patients who were refractory to rescue therapy. A more potent regimen such as ETV-TDF combination therapy may be considered in such refractory cases.
Adenine/*analogs & derivatives/therapeutic use ; Adult ; Aged ; Antiviral Agents/*therapeutic use ; DNA, Viral/analysis/metabolism ; Drug Resistance, Viral ; Drug Therapy, Combination ; Female ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B virus/genetics/isolation & purification ; Hepatitis B, Chronic/*drug therapy/virology ; Humans ; Male ; Middle Aged ; Organophosphonates/*therapeutic use ; Polymerase Chain Reaction ; Republic of Korea ; Retrospective Studies ; Tenofovir/*therapeutic use ; Treatment Outcome