BACKGROUND/AIMS: The efficacy of tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B (CHB) patients following prior treatment failure with multiple nucleos(t)ide analogues (NAs) is not well defined, especially in Asian populations. In this study we investigated the efficacy and safety of TDF rescue therapy in CHB patients after multiple NA treatment failure. METHODS: The study retrospectively analyzed 52 CHB patients who experienced failure with two or more NAs and who were switched to regimens containing TDF. The efficacy and safety assessments included hepatitis B virus (HBV) DNA undetectability, hepatitis B envelop antigen (HBeAg) seroclearance, alanine transaminase (ALT) normalization and changes in serum creatinine and phosphorus levels. RESULTS: The mean HBV DNA level at baseline was 5.4 +/- 1.76 log10 IU/mL. At a median duration of 34.5 months of TDF treatment, the cumulative probabilities of achieving complete virological response (CVR) were 25.0%, 51.8%, 74.2%, and 96.7% at 6, 12, 24, and 48 months, respectively. HBeAg seroclearance occurred in seven of 48 patients (14.6%). ALT levels were normalized in 27 of 31 patients (87.1%) with elevated ALT at baseline. Lower levels of HBV DNA at baseline were significantly associated with increased CVR rates (p < 0.001). However, CVR rates did not differ between TDF monotherapy or combination therapy with other NAs, and were not affected by mutations associated with resistance to NAs. No significant adverse events were observed. CONCLUSIONS: TDF is an efficient and safe rescue therapy for CHB patients after treatment failure with multiple NAs.
Adenine/adverse effects/*analogs & derivatives/therapeutic use ; Adult ; Aged ; Alanine Transaminase/blood ; Antiviral Agents/adverse effects/*therapeutic use ; Biological Markers/blood ; Creatinine/blood ; DNA, Viral/blood ; Drug Resistance, Viral/genetics ; Drug Substitution ; Female ; Genotype ; Hepatitis B e Antigens/blood ; Hepatitis B virus/*drug effects/genetics/immunology/pathogenicity ; Hepatitis B, Chronic/blood/diagnosis/*drug therapy ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Mutation ; Phosphorous Acids/adverse effects/*therapeutic use ; Phosphorus/blood ; Retrospective Studies ; Time Factors ; Treatment Failure ; Viral Load ; Young Adult

Betulinic acid is a naturally occurring pentacyclic triterpenoid, which has antiretroviral, antimalarial, and anti-inflammatory properties. The purpose of this study is to investigate the HBV DNA replication inhibition in the mouse model with betulinic acid. Hydrodynamic injection method via the tail vein with the Paywl. 3 plasmid was used to establish the animal mode (n = 15), and the mice were randomly divided into the PBS control group (n = 5), Betulinic acid treatment group (n = 5) and lamivudine control group (n = 5). The day after successful modeling , the mice would have taken Betulinic acid (100 mg x kg(-1)), lamivudine (50 mg x kg(-1)), PBS drugs orally, once daily for 7 days, blood samples were acquired from the orbital venous blood at 3, 5, 7 days after the administering, HBsAg and HBeAg in serum concentration were measured by ELISA and the mice were sacrificed after 7 days, HBV DNA southern detections were used with part of mice livers. The results showed that betulinic acid significantly inhibited the expression of HbsAg in the mice model at the fifth day compared with the control group, and there was no significant differences between the effects of lamivudine and the PBS control group; both the betulinic acid and lamivudine groups had no significant inhibition for the HBeAg expression; the HBV DNA expressions of the liver tissue from the betulinic acid and lamivudine groups were inhibited compared with the control group. Taken together, these results reveal betulinic acid can inhibit the HBsAg expression and replication of the liver HBV DNA in the mouse model.
Acute Disease ; Animals ; Antiviral Agents ; pharmacology ; DNA Replication ; drug effects ; DNA, Viral ; biosynthesis ; Hepatitis B ; blood ; virology ; Hepatitis B Surface Antigens ; blood ; Hepatitis B virus ; drug effects ; genetics ; immunology ; physiology ; Male ; Mice ; Plasmids ; genetics ; Triterpenes ; pharmacology ; Virus Replication ; drug effects

<b>OBJECTIVEb>To explore the effect of compound qizhu granule (CQG) on cellular immunity of chronic hepatitis B (CHB) patients.

<b>METHODSb>Totally 103 CHB patients treated with lamivudin (LAM) for 6 months, who had partial virological response (HBeAg positive) were randomly assigned to two groups, 50 in the treatment group and 53 in the control group. All patients took LAM 100 mg (once a day) plus ADV 10 mg (once a day). Patients in the treatment group additionally took CQG, one dose per day. After one-year treatment hepatitis B virus (HBV) DNA negative rates, HBeAg seroconversion, levels of HBV specific cytotoxic T lymphocyte (CTL), non-specific CTL and natural killing (NK) cells were compared between the two groups.

<b>RESULTSb>After 1-year treatment, HBV DNA negative rate of the treatment group was 88: 0% in 44 cases, slightly higher than that of the control group (41 cases, 77.4%), but with no statistical difference (P >0.05). HBeAg seroconversion of the treatment group was 32.0% in 16 cases, higher than that of the control group (8 cases, 15.1%), with statistical difference (P <0.05). Levels of HBV specific CTL (0.79%±0. 07%), non-specific CTL (19.4%±1.8%) and NK cells (14. 1%± 1.5%) of the treatment group were higher than those of the control group (0.58% ± 0.08%, 17.5% ± 1.7%, and 11.1%±1.5%, respectively; allP <0.01).

<b>CONCLUSIONb>Treating CHB patients with partial virological response by ADV plus CQG could improve specific and non-specific cellular immunity, thereby elevating HBeAg seroconversion rate.

Drugs, Chinese Herbal ; therapeutic use ; Hepatitis B e Antigens ; immunology ; Hepatitis B virus ; genetics ; Hepatitis B, Chronic ; drug therapy ; immunology ; Humans ; Immunity, Cellular ; immunology ; T-Lymphocytes, Cytotoxic ; drug effects

<b>OBJECTIVEb>To determine the relationship between IgG antibody against the C-terminal region of the preS1 protein of hepatitis B virus and the early response to interferon therapy in chronic hepatitis B.

<b>METHODSb>69 patients with chronic hepatitis B virus (genotype B) infection were recruited in this study. 42 patients were treated with interferon-a-1b or a-2b, and 27 patients were treated with PEG interferon (a-2a). Peptide mimicking the C-terminal region of the preS1 protein (94-117aa) of genotype B HBV were synthesised, and the IgG antibody against this peptide was measured by ELISA, and the early response to IFN-alpha therapy was judged by the effect on the viral kinetics, transaminase and the status of HBeAg at 12th week after the treatment.

<b>RESULTSb>21 patients were positive for anti-preS1 antibody, and 48 patients were negative for anti-preS1 antibody. After 12 weeks of the treatment, the average decrease in viral levels was 3.37log10 copies/ml and 0.33log10 copies/ml in anti-PreS1 positive patients and anti-preS1 negative patients, respectively, the difference between the two groups was significant (Z = -3.658, P = 0.000); the average decrease in ALT levels was 92 U/L and 30.5 U/L in these two groups, respectively (Z = -2.132, P = 0.033). The rate of hepatitis B e antigen (HBeAg) loss was 41.2% (7/17) and the rate of anti-HBe seroconversion was 5.9% (1/17) in anti-PreS1 positive group, however, the rate of hepatitis B e antigen loss was only 12.8% (5/39), and none of the patients in anti-PreS1 negative group showed anti-HBe seroconversion, the difference between the two groups was significant (Z = -5.110, P = 0.000). The rates of response were 71.4% (15/21) and 16.7% (8/48), respectively, in anti-PreS1 positive group and anti-PreS1 negative group. The rates of complete response were 23.8% (5/21) and 6.25% (3/48), respectively, in these two groups. The positive predictive value (PPV) of anti-C-terminal region of preS1 (94-117aa) antibody in predicting early response was 71.6% and the negative predictive value (NPV) was 83.3%. CONCLUCIONS: Detection of anti-C-terminal region of preS1 (94-117aa) antibody may help to improve the efficacy of INF-alpha therapy for chronic hepatitis B (CHB).

Adolescent ; Adult ; Alanine Transaminase ; blood ; Antiviral Agents ; therapeutic use ; DNA, Viral ; blood ; Female ; Hepatitis B Surface Antigens ; blood ; immunology ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; drug effects ; genetics ; Hepatitis B, Chronic ; blood ; drug therapy ; immunology ; Humans ; Immunoglobulin G ; blood ; immunology ; Interferon-alpha ; therapeutic use ; Male ; Polymerase Chain Reaction ; methods ; Predictive Value of Tests ; Prospective Studies ; Protein Precursors ; blood ; immunology ; Viral Load ; Young Adult

To develop a HBV infection mouse model by hydrodynamic-based transfection and further to optimize the method of development of HBV infection mouse model. We first developed a construct which contained inverted terminal repeat elements (ITR) of adeno-associated virus (AAV) and 1. 3 copies of HBV genome (ayw subtype). The pAAV-HBV1. 3 DNA was then injected hydrodynamically into the tail veins of C57BL/6 mice in 5 seconds. The virus load in serum and liver was assayed by ELISA and Real-time PCR. The expression of virus antigen and the pathologic changes of liver were analyzed by HE and immunohistochemical staining. Meanwhile, to develop HBV transfected immunosuppressied mouse, mice were injected intraperitoneally triple with 0.2 ml dexamethason (50 mg/kg) every two days before HBV transfection. The levels of HBsAg and HBeAg were assayed by ELISA. Our data showed: (1) HBsAg and HBeAg were positive (100%) in serum and liver of experimental normal mouse at day 10 after HBV transfection, and became negative at day 30 and day 60. Meanwhile the viral load in serum and liver in experimental group was significantly higher than that in control group at day 10, 30 and 60 after HBV transfection (P < 0.01, P < 0.05, respectively). (2) HBsAg and HBeAg in serum in immunosuppressed mouse model were positive until 60 days. In conclusion, a HBV infection mouse model was developed successfully by hydrodynamic-based transfection. By suppressing the immune status of mice injected with dexamethasone, the expression of HBV antigens was extended longer than that in normal adult mice. These models pave a way for HBV research and evaluation of HBV vaccine and drug development.
Animals ; Dependovirus ; genetics ; metabolism ; Dexamethasone ; administration & dosage ; immunology ; Disease Models, Animal ; Female ; Gene Expression Regulation, Viral ; drug effects ; Genetic Vectors ; genetics ; metabolism ; Hepatitis B ; immunology ; virology ; Hepatitis B Antigens ; genetics ; metabolism ; Hepatitis B virus ; drug effects ; genetics ; physiology ; Humans ; Immunosuppressive Agents ; administration & dosage ; immunology ; Liver ; immunology ; virology ; Mice ; Mice, Inbred C57BL ; Transfection ; methods

<b>OBJECTIVEb>To observe the effect of Chinese medicine therapy for strengthening-Pi and nourishing-Shen (SPNS) in preventing lamivudine induced YMDD mutation and its immunological mechanism.

<b>METHODSb>One hundred and sixty chronic hepatitis B (CHB) patients with positive HBeAg were equally assigned to two groups at random: the observation group and the control group. Patients in the observation group were treated with lamivudine combined with SPNS, and those in the control group were treated with lamivudine only, with the treatment lasting for 52 weeks in total. Changes in indexes, including liver function, HbeAg, HBV-DNA, YMDD variation, CD(4), CD(4)/CD(8) ratio, interferon-gamma (IFN-gamma), interleukin-4 (IL-4), blood routine, renal function, as well as any adverse reactions that occurred in patients, were observed at different time points.

<b>RESULTSb>The ALT, AST recovery rate and HBV-DNA negatively inversing rate at the 24th week, the 36th week and the 52nd week were all higher (P<0.05); meanwhile, the YMDD mutation rate at the 36th week and the 52nd week was lower (P<0.05) in the observation group than in the control group. The posttreatment levels of CD(4), CD(4)/CD(8) ratio, IFN-gamma, and IL-4 as well as the pre-post treatment difference of these indexes in the observation group were significantly different from those in the control group (P<0.05).

<b>CONCLUSIONb>Chinese medicine SPNS therapy can significantly reduce the YMDD variation of HBV, and the mechanism may be related to its regulation of the CD(4) level, CD(4)/CD(8) ratio and Th1/Th2 balance.

Adult ; Antiviral Agents ; adverse effects ; therapeutic use ; DNA, Viral ; genetics ; Drug Resistance, Viral ; drug effects ; genetics ; immunology ; Female ; Genes, Viral ; Hepatitis B virus ; genetics ; immunology ; Hepatitis B, Chronic ; drug therapy ; immunology ; prevention & control ; virology ; Humans ; Immune Evasion ; genetics ; Lamivudine ; adverse effects ; therapeutic use ; Male ; Medicine, Chinese Traditional ; methods ; Middle Aged ; Mutation ; physiology ; Palliative Care ; methods ; Secondary Prevention ; Young Adult

<b>OBJECTIVEb>To study the correlation of HBV genotypes to the response to PEG-interferon alpha (PEG-IFN) in chronic hepatitis B (CHB) patients.

<b>METHODSb>Real-time fluorescent PCR was used for HBV genotyping in 48 CHB patients, and the therapeutic effects of PEG-IFN and hepatic pathological changes were observed.

<b>RESULTSb>No obvious differences were noted in ALT and HBV DNA levels or negative rate for HBeAg between patients with genotypes B and C (P>0.05). The sustained response rate was significantly higher in genotype B than in genotype C patients 48 weeks o after the therapy.

<b>CONCLUSIONb>HBV genotype is the main factor for predicting PEG-IFN therapy response in CHB patients, and the sustained response rate is significantly higher in genotype B than in genotype C patients.

Adolescent ; Adult ; Antiviral Agents ; therapeutic use ; DNA, Viral ; blood ; Female ; Genotype ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; genetics ; immunology ; Hepatitis B, Chronic ; blood ; drug therapy ; virology ; Humans ; Interferon-alpha ; therapeutic use ; Liver ; drug effects ; pathology ; virology ; Male ; Middle Aged ; Polyethylene Glycols ; therapeutic use ; Recombinant Proteins ; Young Adult

<b>OBJECTIVEb>To observe the changes of replication and antigen expressions of lamivudine-resistant hepatitis B virus (HBV) with polymerase gene mutation.

<b>METHODSb>With site-directed mutagenesis, we constructed 3 HBV plasmids with polymerase gene mutation based on the template P3.8II. All the plasmids were transfected into HepG2 cells, in which the replication and expression of the virus were analyzed.

<b>RESULTSb>The 3 polymerase gene mutant HBVs were successfully constructed. HBsAg and HBeAg expressions were detected in the supernatants of HepG2 cells transfected with these plasmids. The replication of the 3 mutant plasmids with rtG172E, rtG174C and rtG172E/rtG174C mutation decreased significantly in comparison with the wild-type virus.

<b>CONCLUSIONb>The 3 polymerase gene mutant HBVs shows depressed capacity for viral replication, and in vitro drug sensitivity study is needed to establish the relationship between these mutations and nucleoside analogue resistance.

Base Sequence ; Drug Resistance, Viral ; genetics ; Gene Expression ; Genetic Engineering ; methods ; Genome, Viral ; genetics ; Hep G2 Cells ; Hepatitis B Surface Antigens ; genetics ; Hepatitis B e Antigens ; genetics ; Hepatitis B virus ; drug effects ; genetics ; immunology ; physiology ; Humans ; Lamivudine ; pharmacology ; Mutation ; Plasmids ; genetics ; Transfection ; Virus Replication ; genetics

<b>OBJECTIVEb>To evaluate the advantages of combination therapy with interferon-alpha plus nucleoside analogue-lamivudine or HBV vaccine in children with HBeAg positive chronic hepatitis B.

<b>METHODSb>A total of 120 patients with HBeAg positive chronic hepatitis B were divided into three groups, 40 patients per group. Each group was treated with one of the following therapies respectively: Group A IFN-alpha 1b 10 MU/m2 three times per week (Tiw); Group B IFN-alpha 1b 10MU/m2 three times per week (Tiw) plus lamivudine 3 mg/kg for 6 months. Group C IFN-alpha 1b 10 MU/m2 three times per week (Tiw) plus HBV vaccine 30 microg one a month.

<b>RESULTSb>There was no significant difference in normalizing rate of ALT among the three groups at end of treatment. There was more significant difference in negative rate (seroconversion) of serum HBV DNA and HBeAg in group B than group A and group C (P less than 0.05).

<b>CONCLUSIONb>The combination therapy of IFN-alpha 1b plus lamivudine seemed to be more effective than the therapy with IFN-alpha alone and the combination of IFN-alpha and HBV vaccine.

Anti-HIV Agents ; therapeutic use ; Child ; Child, Preschool ; DNA, Viral ; blood ; Drug Therapy, Combination ; Female ; Follow-Up Studies ; Hepatitis B Vaccines ; therapeutic use ; Hepatitis B e Antigens ; blood ; genetics ; immunology ; Hepatitis B virus ; drug effects ; genetics ; immunology ; Hepatitis B, Chronic ; blood ; drug therapy ; Humans ; Interferon-alpha ; therapeutic use ; Lamivudine ; therapeutic use ; Male ; Treatment Outcome

<b>OBJECTIVEb>To determine the relationship between the response to adefovir dipivoxil (ADV) treatment in patients with HBV genotypes B and C of HBeAg positive chronic hepatitis B.

<b>METHODSb>This clinical trial was a randomized, double-blind, placebo-controlled, multicenter study. A total of 226 eligible patients with HBeAg positive chronic hepatitis B were randomized (in a ratio of 2:1) receiving ADV 10 mg/d for 48 weeks (ADV+ADV group) or placebo for 24 weeks followed by ADV 10 mg/d for 24 weeks (PLB+ADV group). The primary efficacy was virologic response. The genotypes of HBV were determined by PCR-restricted fragment length polymorphism (RFLP) method using serum samples before therapy. rtN236T and rtA181V mutations were confirmed by sequencing.

<b>RESULTSb>In this study, HBV genotype C was 66.7%, genotype B was 25.2%. Genotype B was more common in Guangzhou. Patients with genotype B were much younger than those with the genotype C. Patients with genotype B previously received less anti-HBV therapy. There were no significant difference in virological response (including mean reduction in HBV DNA level from baseline, serum HBV DNA load after treatment and HBV DNA undetectable rate) and serological response (the rate of HBeAg loss and HBeAg seroconversion) between patients infected with genotypes B and C in both treatment arms.

<b>CONCLUSIONb>There were no significant difference in virological and serological response to ADV therapy between patients infected with HBV genotype B and C.

Adenine ; analogs & derivatives ; therapeutic use ; Adolescent ; Adult ; Antiviral Agents ; therapeutic use ; DNA, Viral ; blood ; genetics ; Double-Blind Method ; Female ; Genotype ; Hepatitis B Antibodies ; blood ; Hepatitis B e Antigens ; immunology ; Hepatitis B virus ; drug effects ; genetics ; immunology ; Hepatitis B, Chronic ; blood ; drug therapy ; virology ; Humans ; Male ; Middle Aged ; Organophosphonates ; therapeutic use ; Treatment Outcome ; Young Adult