Adefovir Dipivoxil plus Chinese Medicine in HBeAg-Positive Chronic Hepatitis B Patients: A Randomized Controlled 48-Week Trial / 中国结合医学杂志

OBJECTIVE@#To evaluate the effects of a 48-week course of adefovir dipivoxil (ADV) plus Chinese medicine (CM) therapy, namely Tiaogan Jianpi Hexue () and Tiaogan Jiedu Huashi () fomulae, in hepatitis B e antigen (HBeAg)-positive Chinese patients.@*METHODS@#A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group (EG, received ADV plus CM) and control group (CG, received ADV plus CM-placebo) for 48 weeks. The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12, 24, 36, 48, respectively. Secondary endpoints including liver functions (enzymes and bilirubin readings) were evaluated every 4 weeks at the beginning of week 24, 36, and 48. Routine blood, urine, and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations. Adverse events (AEs) were documented.@*RESULTS@#The combination therapy demonstrated superior HBeAg loss at 48 weeks, without additional AEs. The full analysis population was 560 and 280 in each group. In the EG, population achieved HBeAg loss on week 12, 24, 36, and 48 were 25 (8.90%), 34 (12.14%), 52 (18.57%), and 83 (29.64%), respectively; the equivalent numbers in the CG were 20 (7.14%), 41 (14.64%), 54 (19.29%), and 50 (17.86%), respectively. There was a statistically significant difference between these group values on week 48 (P<0.01). No additional AEs were found in EG. Subgroup analysis suggested different outcomes among treatment patterns.@*CONCLUSION@#Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy. The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile (ChiCTR-TRC-11001263).

Study on Pharmacokinetics of Metabolites of Adefovir in Rats after Intragastric Administration of Adefovir Derivatives / 中国药房

OBJECTIVE： To establish a method for the determination of adefovir （PMEA） and study the pharmacokinetics of metabolites PMEA in rats after intragastric administration of PMEA derivatives [PMEA prodrug， adefovir-ursodeoxycholic acid-3-propyl ester， L-leucine-3-propyl ester （PMEA-1c）] in rats. METHODS： HPLC-MS/MS method was adopted. The determination was performed on BEH C18 column with mobile phase consisted of 0.1％ formic acid acetonitrile-0.1％ formic acid water （gradient elution） at the flow rate of 0.25 mL/min. The column temperature was 30 ℃， and sample size was 1 μL. The quantitative ions were PMEA m/z 274.1→162.1， puerarin （internal standard） m/z 417.1→267.1. 12 rats were randomly divided into adefovir dipivoxil （ADV） group （positive control， 90 mg/kg） and PMEA-1c group （160 mg/kg）， with 6 rats in each group. They were given relevant medicine once intragstrically， and the blood samples were collected from tail vein 0.083， 0.25， 0.5， 0.75， 1， 2， 4， 6， 8， 10， 12， 24 h after administration to determine the plasma concentration of PMEA. Relevant pharmacokinetic parameters were calculated by using DAS 2.0 software. RESULTS： The linear range of PMEA was 6.1-440.0 ng/mL （r＝0.998 5）. RSDs of intra and inter day of precision and stability tests were all less than 10％ （n＝3， 5， 6）， and the accuracy was 82.16％-97.33％ （RSD≤6.4％， n＝5）. Matrix effects ranged from 95.96％-106.35％ （RSD≤4.9％， n＝5）. The pharmacokinetic parameters of PMEA in ADV group and PMEA-1c group were as follows as t1/2 were （1.762±0.117） and （2.548±0.174） h； AUC0-24 h were （2 170.059±146.091） and （4 704.257±176.792） μg·h/L； cmax were （613.092±9.504） and （697.295±15.275） μg/L， respectively. Compared with ADV group， t1/2， AUC0-24 h， AUC0-∞ and cmax of rats in PMEA-1c group were increased significantly （P＜0.01 or P＜0.001）. CONCLUSIONS： Established method is accurate and reliable. The trial indicates that PMEA-1c metabolism is single compartment model， show that can be used as a potential prodrug for adefovir， which lay a foundation for the further study of adefovir prodrug.

Lamivudine plus tenofovir versus lamivudine plus adefovir for the treatment of hepatitis B virus in HIV-coinfected patients, starting antiretroviral therapy

Background: Combination of tenofovir disoproxil fumarate (TDF), lamivudine (3TC) and efavirenz (EFV) is preferred in the treatment of HIV/hepatitis B virus (HBV) coinfection. We postulated that a HBV active nucleoside reverse transcriptase (RT) inhibitor/nucleotide RT inhibitor backbone of adefovir dipivoxil (ADV) +3TC would be as effective as TDF +3TC for the Indian population. Objective: ADV + 3TC could be an alternative option for these HIV/HBV coinfected individuals, preserving the dually active TDF + 3TC as second-line nucleoside backbone following failure of the first-line ART. Materials and Methods: This randomised control trial (CTRI/2012/03/002471) was carried out at the ART Centre of Calcutta School of Tropical Medicine, India. Seventy-eight (39 on each arm) treatment-naïve HIV/HBV coinfected patients were randomised to receive either the combination of lamivudine + tenofovir + EFV or lamivudine + adefovir + zidovudine + EFV and followed up for 120 weeks. Results: Median age of the study participants was 36 years (21–62), majority were male (61/78; 78.2%) and heterosexually (39/78; 50%) infected. Baseline characteristics were identical in both arms. There was no statistically significant difference in median aspartate aminotransferase (37 vs. 29.5 U/L), alanine aminotransferase (ALT) (36 vs. 34.5 U/L), ALT normalisation rate (80 vs. 70%), AST to platelet ratio index (0.45 vs. 0.33), CD4 count (508 vs. 427 cells/mm3), HBV DNA suppression (81.8 vs. 70%), hepatitis B e antigen loss (9 vs. 5%), hepatitis B surface antigen seroclearance rate (6.06 vs. 18.75%) and death (3 vs. 3) at 120 weeks between TDF (n = 33) and ADV (n = 32), respectively. Conclusions: Adefovir plus lamivudine is an effective alternative of tenofovir plus lamivudine in long-term HBV treatment outcome in HIV/HBV coinfected patients.

In vitro metabolism and stability of adefovir mixed phosphonate derivative Q3-I2 / 中国药科大学学报

@#A, UPLC-QTOF-MS/MS and UPLC-MS/MS were used to investigate the derivative of adefovir mixed phosphonate Q3-I2. Stability and in vitro metabolites of Q3-I2, and the control drug adefovir dipivoxil were co-inculbated with artificial gastric juice, artificial intestinal juice, rat blank plasma and rat liver microsomes, using UPLC-MS/MS and UPLC-QTOF-MS/MS measure the residual concentration of the compounds in each incubation system and the metabolites in the liver microsomal system, respectively, and calculate the half-life and clearance rate by the substrate elimination method. The compounds designed and synthesized in this experiment are stable in the gastrointestinal tract, prolonging t1/2 of plasma and liver microsomes and rapidly degrading the active meta-bolites. In the liver microsomal system, a total of 8 metabolites were detected by positive and negative ion mode, including hydrolysis, oxidation, acetylation, and glucuronidation.

Compare the effect of combined therapy between telbivudine plus adefovir dipivoxil and lamivudine plus adefovir dipivoxil corresponding to renal function in patients with hepatitis B virus infection / 中华肝脏病杂志

Objective@#To compare the effect of combined therapy using lamivudine (LAM) plus adefovir (ADV) versus telbivudine (LdT) plus adefovir corresponding to the renal function of CHB patients.@*Methods@#A total of 120 patients with chronic hepatitis B were enrolled. According to single daily dosing, they were divided into 4 groups: LdT + ADV group (n = 32), ADV+LdT group (n = 28), LAM + ADV group (n = 38) and ADV + LAM group (n = 22). Hepatorenal function, HBV serological markers, HBV DNA quantification, creatine kinase (CK) and other parameters were examined every 3 months. Serum alanine aminotransferase (ALT) normalization rate, undetectable HBV DNA rate, hepatitis B e antigen (HBeAg) seroconversion rate, level of serum creatinine (CR) and estimated glomerular filtration rate (eGFR) were analyzed at baseline time, and at weeks 24 and 52.Stastical data were analyzed by t- test and analysis of variance, count data using χ 2 test.@*Results@#There was no statistically significant difference between the four groups in terms of ALT normalization rate, HBeAg seroconversion rate, undetectable HBV DNA rate at 24 and 52 weeks. Compared with baseline, at 24 weeks of treatment, there was no significant change in serum creatinine and eGFR in the 4 groups, but after 52 weeks of treatment, serum creatinine decreased in LdT + ADV and ADV + LdT groups and eGFR increased (P < 0.05); Serum creatinine in ADV and ADV + LAM increased, and eGFR was decreased than before (P < 0.05). After treatment, there was no significant difference in renal function between the four groups at 24 weeks, but at week 52, eGFR increased and serum creatinine decreased in LdT + ADV group compared with LAM + ADV group (P < 0.05); ADV + LdT Compared with ADV + LAM group, eGFR increased and serum creatinine decreased (P < 0.05). At 52 weeks of treatment, 5 patients with mildly impaired renal function in the ADV + LdT group [n = 10, eGFR 60-90 ml·min-1 ·(1.73 m2)-1] returned to normal, and none of the ADV + LAM group (n = 9) returned to normal.@*Conclusion@#For patients with mild impaired renal function, adding LdT combined with ADV can improve renal function compared to that of LAM plus ADV.

Adefovir-induced Fanconi syndrome associated with osteomalacia

Fanconi syndrome is a dysfunction of the proximal renal tubules that results in impaired reabsorption and increased urinary loss of phosphate and other solutes. The pathophysiology of drug-induced Fanconi syndrome is unclear. Here we report the case of a 36-year-old woman who presented with pain in multiple bones and proteinuria. She had a 7-year history of taking adefovir at 10 mg/day for chronic hepatitis B. Three years previously she had received surgery for a nontraumatic right femur neck fracture, after which she continued to complain of pain in multiple bones, and proteinuria, glycosuria, and phosphaturia were noted. The findings of a light-microscope examination of a renal biopsy sample were normal, but mitochondrial damage of the proximal tubules was evident in electron microscopy. Western blot analysis revealed that the level of serum fibroblast growth factor 23 (FGF23) was lower than in normal controls. After 2 months of treatment, hypophosphatemia and proximal tubular dysfunction were reversed, and serum FGF23 had normalized. This case suggests that direct mitochondrial damage in proximal tubules can cause drug-induced Fanconi syndrome associated with osteomalacia.

Enhanced dissolution and intestinal absorption of adefovir dipivoxil by cocrystal formation with acetaminophen / 药学学报

In current study, adefovir dipivoxil (AD)-acetaminophen (AP) cocrystal (molar ratio, 1:1) was prepared by slow evaporation from acetonitrile, followed by physicochemical characterizations using differential scanning calorimetry, powder X-Ray diffraction and Fourier transform infrared spectroscopy. Molecular modeling showed that the phosphoester group of AD was connected with the amide group of AP through hydrogen bonds. In comparison to crystalline AD, the solubility and dissolution rate of AD from AD-AP cocrystal were significantly enhanced by 1.5-fold and 1.6-fold, respectively. In addition, based on the rat single-pass intestinal perfusion study, the permeabilities of AD in various intestinal sections (i.e., duodenum, jejunum, ileum and colon) were significantly improved (e.g., about 3-fold enhancement in duodenum) after cocrystallization with AP by inhibiting P-glyprotein mediated efflux of AD, which will benefit absorption in vivo and subsequent oral bioavailability of poorly permeable drug AD.

Synthesis and bioactivity of mixed phosphonate derivatives of adefovir with hepatic targeting property / 中国药科大学学报

In order to search for new adefovir analogues as anti-HBV agents with enhanced antiviral activity and hepatotrophic property,adefovir bis L-amino acid ester was used as lead compound to produce ten adefovir mono L-(thio)amino acid ester, mono bile acid ester derivatives(6a-6j). The design based on bile acid prodrug strategy,which can improve drug oral bioavaliability and liver-targeted enrichment by using enterohepatic circula-tion of bile acid.Sub-structure combination method was adopted to introduce L-(thio)amino acid ester and bile acid ester fragments on the phosphonate functionality of adefovir. The structures of target compounds were confirmed by 1H NMR, 13C NMR,ESI-MS and ESI-HRMS.HepG 2.2.15 cell were used for in vitro anti-HBV activity assessment.Compound 6c with high antiviral activity(EC500.92μmol/L,SI 512.63)was further investi-gated for its tissue distribution in mice.The results showed that content of compound 6c in liver was higher than that of adefovir dipivoxil,and in contrast its content in kidney was lower than that in positive control at all time points(0.25-12 h).Compound 6c exhibits higher antiviral activity,selective index and higher liver distribution,making it a potential anti HBV agent for further investigation.

Effects of telbivudine and entecavir on improvement of renal function in chronic hepatitis B patients with renal impairment after adefovir dipivoxil treatment / 中国医师进修杂志

Objective To explore the effects of telbivudine (LdT) and entecavir (ETV) on renal function in chronic hepatitis B (CHB) patients with renal damage after adefovir dipivoxil (ADV) treatment. Methods The clinical data of 40 CHB patients with renal damage after ADV treatment from January 2015 to February 2016 were retrospectively analyzed. The patients were divided into 2 groups according to the substitution drugs. Twenty patients in ETV group received ETV replacement therapy, and 20 patients in LdT group received LdT replacement therapy. The serum alanine aminotransferase (ALT), serum creatinine, serum creatine kinase (SCK), urinary β2-microglobulin (Uβ2-MG), estimated glomerular filtration rate (eGFR), classification of renal function, improvement of renal function and positive rate of HBV-DNA were compared between 2 groups. Results There was no statistical difference in serum ALT between 2 group (P＞0.05). The serum creatinine, SCK, Uβ2-MG and eGFR levels after treatment in LdT group were significantly better than those in ETV group: (92.08 ± 9.35) μmol/L vs. (101.21 ± 10.31) μmol/L, (133.69 ± 31.29) U/L vs. (106.14 ± 26.19) U/L, (5 126.17 ± 415.79) μg/L vs. (6 381.92 ± 574.12) μg/L and (81.61 ± 20.52) ml/(min·1.73 m2) vs. (75.34 ± 19.67) ml/(min·1.73 m2), and there were statistical differences (P＜0.05). There was no statistical difference in the positive rate of HBV-DNA after treatment between 2 groups (P＞0.05). The abnormal rate of renal function classification after treatment in LdT group was significantly lower than that in ETV group: 0 vs. 20.0% (4/20), the improvement rate of renal function in ETV group was significantly higher than that in ETV group: 100.0% (20/20) vs. 80.0% (16/20), and there were statistical differences (P＜0.05). Conclusions The effect of LdT on renal function improvement in CHB patients with renal damage after ADV treatment is more obvious than that of ETV, which can significantly improve serum creatinine, SCK, Uβ2-MG and eGFR, and reduce the abnormal renal function.

Hypophosphatemic osteomalacia caused by adefovir dipivoxil: case report and literature review / 中华全科医师杂志

A 61-years male patients with chronic hepatitis B developed hypophosphatemic osteomalacia following long-term use of adefovir dipivoxil in our hospital.With "adefovir dipivoxil" and "osteomalacia" as the search terms,we searched Wanfang database and Chinese Biomedical bibliographic database since 2005,and retrieved 79 cases of adefovir dipivoxil-induced hypophosphatemic osteomalacia.Of the 80 cases,there were 63 males and 17 females with a mean age of (52 ± 11) years.The average duration of disease to first diagnosis made was 17 months,the average duration of adefovir dipivoxil administration to the onset of the disease was 62 months,and the average duration of hepatitis B was 11 years.The most common clinical manifestation was progressive bone pain in all parts of the body (80/80 cases);the most common laboratory finding was decreased serum phosphorus (80/80 cases),followed by abnormal urine tests (55/56 cases) including increased urinary phosphorus,urinary protein and positive urinary occult blood.The X-ray,CT and MRI showed different degrees of decreased bone density,osteoporosis,and bone fracture in severe patients (76/77 cases).It is suggested that clinicians should pay attention to the renal damage during the treatment of adefovir dipivoxil,and the renal function,electrolyte and bone density should be monitored regularly.

Comparison of efficacy and safety between entecavir versus adefovir dipivoxil in the treatment of HBeAg positive chronic hepatitis B / 中国综合临床

Objective To compare the efficacy and safety of entecavir versus adefovir dipivoxil in the treatment of HBeAg positive chronic hepatitis B ( CHB) . Methods Ninety?six cases with HBeAg positive CHB were divided into ETV group and ADV group according to different medication. In addition to conventional treatment,ETV group received entecavir 0. 5 mg/d,ADV group received adefovir dipivoxil 10 mg/d. HBV DNA negative conversion rate,alanine aminotransferase ( ALT) recurrence rate and HBeAg negative conversion rate in 24 weeks,48 weeks and 96 weeks were compared as well as the adverse reactions and liver function in 96 weeks. Results HBV DNA negative conversion rates in ETV group were significantly higher than those in ADV group in 24 weeks,48 weeks and 96 weeks (24 weeks:64. 6％(31/48) vs. 41. 7％(20/48);48 weeks:83. 3％(40/48) vs. 52. 1％(25/48);96 weeks:97. 9％(47/48) vs. 62. 5％(30/48),χ2 =5. 06,10. 72,18. 96,P<0. 05) . ALT recurrence rates in ETV group were significantly higher than those in ADV group at 24 weeks,48 weeks ( 24weeks:77. 1％( 37/48 ) vs. 54. 2％( 26/48 );48weeks:85. 4％( 40/48 ) vs. 62. 5％( 30/48 ) ,χ2=5. 59,6. 54,P<0. 05). There was no significant difference in ALT complication rate at 96 week(χ2=0. 71,P>0. 05) . There was no significant difference in HBeAg negative conversion rate between the two groups through treatment(χ2=0. 07, 0. 22, 0. 44, P>0. 05 ) . After 96 weeks, ALT in both groups decreased significantly ( t =13. 56,11. 85,P<0. 05) ,while ALT in ETV group was significantly lower than that in ADV group ( ( 31. 8 ±8. 6) U/L vs. (38. 5±7. 5) U/L,t=4. 07,P<0. 05). AST in both groups decreased significantly(t=41. 27, 33. 68,P<0. 05),while AST in ETV group was significantly lower than that in ADV group ( (30. 3±6. 5) U/L vs.(37.6±7.1)U/L,t=5.25,P<0.05).TBIL in both groups decreased significantly(t=28.92,22.23,P<0. 05),while TBIL in ETV group was significantly lower than that in ADV group ( (13. 5±3. 3) μmol/L vs. (18. 7±3. 9) μmol/L,t=7. 05,P<0. 05). GGT in both groups decreased significantly (t=16. 99,13. 97,P<0.05),while GGT in ETV group was significantly lower than that in ADV group ( (35.6±10.4)U/L vs. (59. 7±12. 5)U/L,t=10. 27,P<0. 05). There was no significant difference in adverse reaction between the two groups (χ2=1. 96,P>0. 05) . Conclusion Entecavir has a higher rate of HBV DNA negative conversion rate, ALT recurrence rate and HBeAg negative conversion rate in the treatment of HBeAg positive CHB. It is an ideal antiviral drug.

Systematic evaluation of Compound Biejia Ruangan Tablets combined with Adefovir Dipivoxil in treatment of chronic hepatitis B with liver fibrosis / 中草药

To evaluate the clinical curative effect of Compound Biejia Ruangan Tablets (CBRT) combined with Adefovir Dipivoxil in the treatment of chronic hepatitis B with liver fibrosis using Meta-analysis. Cochrane library, PubMed, CNKI, Wanfang databases, and VIP were retrieved comprehensively to collect randomized controlled trials (RCTs) of CBRT combined with Adefovir Dipivoxil in the treatment of chronic hepatitis B with hepatic fibrosis from their inception to October 2017. treatment group was treated with CBRT combined with Adefovir Dipivoxil, and the control group was treated with Adefovir Dipivoxil. All the data were analyzed using Revman 5.3. A total of 19 RCTs and 1 776 patients were included. Meta-analysis results showed that the serum indexes including HA, IV-C, LN, PCIII, ALT, AST, and TBIL of the treatment group, were significantly lower than those of control group. HA [SMD = -1.72, 95% CI (-2.26, -1.17), P = 0.000 01]; IV-C [SMD = -1.10, 95% CI (-1.66, -0.54), P = 0.000 10]; LN [SMD = -1.18, 95% CI (-1.64, -0.73), P = 0.000 01]; PCIII [SMD = -1.52, 95% CI (-1.97, -1.07), P = 0.000 01]; ALT [SMD =-0.48, 95% CI (-0.68, -0.28), P = 0.000 01]; AST [SMD = -1.19, 95% CI (-2.08, -0.29), P = 0.010 00]; TBIL [SMD = -0.98, 95%CI (-1.38, -0.58), P = 0.000 01]; There were no significant difference in serum HBV DNA, and HbeAg negative conversion rate treatment group compared with control group. HBV DNA [RR = 1.21, 95% CI (0.97, 1.50), P = 0.09]; HBeAg [RR = 1.05, 95% CI (0.82, 1.34), P = 0.70]; The total clinical effective treatment group was significantly better than control group. [RR = 1.25, 95% CI (1.15, 1.36), P = 0.000 01]. Compared with the single use of Adefovir Dipivoxil, the clinical curative effect of CBRT combined with Adefovir Dipivoxil in the treatment of chronic hepatitis B with liver fibrosis is better,which can significantly reduce the level of serum liver fiber markers and improve liver function in patients with biochemical indicators and the total clinical efficiency.

Predictors for Efficacy of Combination Therapy with a Nucleos(t)ide Analogue and Interferon for Chronic Hepatitis B / 华中科技大学学报（医学）（英德文版）

This study aims to explore the efficacy of interferon-α (IFN-α) combined with either entecavir (ETV) or adefovir (ADV) therapy versus IFN-α mono-therapy for chronic hepatitis B (CHB) patients,and to identify the factors associated with treatment outcomes.Totally,159 CHB patients receiving interferon-based treatment for 48 weeks were enrolled in this retrospective study,including IFN-α mono-therapy group (group A,n=44),IFN-α plus ADV group (group B,n=53) and IFN-α plus ETV group (group C,n=62).The primary measures of efficacy assessments were the changes in HBsAg.Cox regression analysis was used to identify the predictors of treatment outcomes.The predictive values of the factors were assessed by ROC analysis.For patients with baseline hepatitis B surface antigen (HBsAg) level ＜1000 IU/mL,the reductions in mean HBsAg levels at week 48 were greater in group C than that in group A (P＜0.05).Higher rate of HBeAg seroconversion was achieved in the combined therapy group than in IFN-α mono-therapy group at week 48 (P＜0.05).Two factors were independently associated with HBeAg seroconversion:baseline HBeAg level ＜2.215 log10 index/mL and △HBeAg (.decline in HBeAg from baseline) ＞0.175 log10 at week 12.In conclusion,interferon-α plus ETV therapy can accelerate HBsAg decline as compared with interferon-α mono-therapy in CHB patients with lower baseline HBsAg levels,and the combination therapy was superior to IFN-α mono-therapy in increasing the rate of HBeAg seroconversion.Baseline HBeAg and △HBeAg at week 12 can independently predict HBeAg seroconversion in patients subject to interferon-based therapy for 48 weeks.

Efficacy of antiviral/immunomodulatory therapy for naive patients with HBeAg-positive chronic hepatitis B / 中华临床感染病杂志

Objective To evaluate the clinical efficacy of interferon(IFN) α-2b,adefovir dipivoxil (ADV),granulocyte-macrophage colony stimulating factor (GM-CSF) and hepatitis B vaccine in the treatment of patients with HBeAg-positive chronic hepatitis B (CHB).Methods Two hundredand forty HBeAg-positive CHB patients admitted in the First Affiliated Hospital,Zhejiang University School of Medicine during November 2013 and December 2015 were retrospectively reviewed.They were randomly assigned to four groups with 60 cases in each group,to receive IFNα-2b (group A),IFNα-2b + ADV (group B),IFNα-2b + ADV + GM-CSF (group C) or IFNoα-2b + ADV + GM-CSF + hepatitis B vaccine (group D) for treatment,respectively.All patients were treated for 48 wks and then followed up for 24 wks.The HBsAg serological response,HBeAg serological response,virological response,biochemical response,histological response and adverse effects were compared among 4 groups.Results After 48-wk treatment,the HBsAg negative conversion rate of group D was significantly higher than that of group A and B (x2 =8.634 and 8.634,both P ＜ 0.01);the seroconversion rate of HBsAg in group D was significantly higher than that in group A and group B (x2 =7.149 and 7.149,both P ＜0.01).The baseline drop rate of HBsAg in group C and D was higher than that in group A (t =4.194 and 4.508,both P ＜0.01).In 24-wk follow-up,HBsAg negative conversion rate was as same as that after 48-wk treatment;the seroconversion rate of HBsAg in group D was significantly higher than that in group A and B (x2 =8.634 and 8.634,both P ＜0.01).The baseline drop rate of HBsAg in group C and group D was higher than that in group A (t =4.546 and 4.969,both P ＜0.01).After 48-wk treatment,the HBeAg negative conversion rate in group D was significantly higher than that in group A (x2 =8.792,P ＜ 0.01);the HBeAg seroconversion rate of group C and D was higher than that of group A (x2 =7.064 and 10.159,P ＜0.01).In 24-wk follow-up,the HBeAg negative conversion rate in group C and D was higher than that in group A (x2 =10.159 and 13.713,P ＜0.01);the HBeAg negative conversion rate in group D was higher than that in group B (x2 =8.155,P ＜0.01);the seroconversion rate of HBeAg in group C and D was higher than that in group A (x2 =10.506 and 12.857,P ＜ 0.01).After 48-wk treatment,the negative rate of HBV DNA in group B,C and D was significantly higher than that in group A (x2 =12.452,17.062 and 20.670,all P ＜0.01).In the 24-wk follow-up,the negative rate of HBV DNA in group B,C and D was also significantly higher than that in group A (x2 =21.121,26.880 and 33.611,all P ＜ 0.01).After 48-wk treatment,the alanine aminotransferase (ALT) normalization rate of the group of C and D was significantly higher than that in group A (x2 =8.711 and 8.711,both P ＜0.01).In the 24-wk follow-up,the ALT normalization rate in group C and D was significantly higher than that in group A (x2 =8.076 and 9.624,P ＜0.01).After 48-wk treatment,the improvement rate of inflammation or fibrosis in the group of A,B and C was significantly higher than that in the group A (x2 =8.543,13.348 and 16.205,all P ＜ 0.01).There were no half-way withdrawal and no serious adverse reactions.The main adverse reactions were fever,headache and fatigue,and no significant difference of above reaction was observed among 4 groups (P ＞ 0.05).Conclusion The new anti-virus/immunoregulation therapy containing IFNα-2b + ADV + GM-CSF + hepatitis B vaccine has a better therapeutic effect for patients with HBeAg-positive CHB.

Formula Optimization of Adefovir Dipivoxil Tablets by D-optimal Mixture Design / 中国药师

Objective:To optimize the formula of adefovir dipivoxil tablets and investigate the dissolution in vitro. Methods:The formula was optimized by the D-optimal mixture design, the effects of the amount of filler ( X1 ,%) , the amount of disintegrant agent ( X2 ,%) and the amount of binder ( X3 ,%) were selected as the independent variables, and the friability ( Y1 ,%) , disintegration time ( Y2 , min) and dissolution of adefovir dipivoxil ( Y3 ,%) were the dependent variables. The similarity of the self-prepared prepa-ration and the reference preparation was obtained by using f2 similarity factor. The stability of adefovir dipivoxil tablets was evaluated preliminarily by high temperature, high humidity and strong light testing. Results:The optimal formula of adefovir dipivoxil tablets was as follows:the amount of lactose monohydrate was 67. 0%, the weight of croscarmellose sodium was 8. 0% and the amount of pregelati-nized starch was 12. 0%. The prepared tablets had lower friability, shorter disintegration time and higher drug dissolution rate. The dissolution similarity factors of the self-prepared tablets and the reference preparation in four dissolution media were all greater than 50. The results of influencing factor tests showed that the product should be moisture preservation. Conclusion:The formula of adefovir dip-ivoxil tablets optimized by the D-optimal mixture design is similar to that of the reference preparation, and the preparation process is feasible, which can meet the requirements of large production.

Influence of combination mode of PEG - IFNα - 2a and adefovir dipivoxil on outcome of patients with HBeAg - posi-tive chronic hepatitis B / 临床肝胆病杂志

Objective To investigate the influence of the sequence of PEG - IFNα - 2a and adefovir dipivoxil (ADV)on the clinical out-come of patients with HBeAg - positive chronic hepatitis B (CHB). Methods A total of 86 patients with HBeAg - positive CHB who were treated in Yucheng People's Hospital from September 1,2011 to November 1,2013 were enrolled and randomly divided into groups A (28 patients,among whom one dropped out in the late stage),B (29 patients,among whom two dropped out in the late stage),and C (29 pa-tients,among whom three dropped out in the late stage). All patients were treated with PEG - IFNα - 2a combined with ADV;the patients in group A were given PEG - IFNα - 2a and ADV concurrently,those in group B were given PEG - IFNα - 2a for 24 weeks,followed by PEG - IFNα - 2a combined with ADV,and those in group C were given ADV for 24 weeks,followed by PEG - IFNα - 2a combined with ADV. The course of treatment was 60 weeks for all groups. The patients were followed up for 24 weeks after drug withdrawal. The three groups were compared in terms of clinical outcome [HBeAg disappearance rate and seroconversion rate,HBsAg clearance rate,HBV DNA clearance rate,and alanine aminotransferase (ALT)normalization rate]. An analysis of variance or t test was used for comparison of contin-uous data between groups,and the chi - square test was used for comparison of categorical data between groups. Results After 60 weeks of treatment,there were significant differences in HBeAg disappearance rate and seroconversion rate between the three groups (85. 2% vs 81. 5% vs 69. 2%,χ2 = 6. 253,P < 0. 05),and groups A and B had significantly higher rates than group C (all P < 0. 0125);there was a significant difference in HBV DNA clearance rate between the three groups (81. 5% vs 55. 6% vs 80. 8%,χ2 = 7. 409,P < 0. 05),and groups A and C had a significantly higher rate than group B (both P < 0. 0125);there was a significant difference in ALT normalization rate between the three groups (81. 5% vs 80. 8% vs 57. 7%,χ2 = 7. 425,P < 0. 05),and group A had a significantly higher rate than group C (P < 0. 0125). After 24 weeks of drug withdrawal,there were significant differences in HBeAg disappearance rate and seroconversion rate between the three groups (81. 5% vs 81. 5% vs 65. 4%,χ2 = 6. 723,P < 0. 05),and groups A and B had significantly higher rates than group C (all P < 0. 0125);there was a significant difference in ALT normalization rate between the three groups (81. 5% vs 74. 1% vs 53. 8%,χ2 = 9. 690,P < 0. 05),and group A had a significantly higher rate than group C (P < 0. 0125). Most adverse reactions occurred within 24 weeks of treatment and mainly manifested as influenza - like symptoms such as low - grade fever,headache,and sore muscle,and most of the patients were relieved spontaneously without intervention. Some patients experienced bone marrow suppression manifesting as re-ductions in leukocytes,neutrophils,and platelets and were relieved after the treatment with granulocyte colony - stimulating factor. Conclu-sion ADV given at first to reduce HBV DNA and followed by the addition of PEG - IFNα - 2a can achieve a similar effect as ADV given concurrently with PEG - IFNα -2a and has certain significance in shortening the duration of PEG - IFNα -2a treatment and reducing the dose of PEG - IFNα -2a.

Clinical investigation of entecavir combined with adefovir dipivoxil in the treatment of adefovir-resistant hepatitis B cirrhosis / 中国基层医药

Objective To investigate the clinical effect of entecavir(ETV) combined with adefovir dipivoxil (ADV) in the treatment of adefovir-resistant hepatitis B cirrhosis.Methods 125 cases of liver cirrhosis with adefovir-resistantce were selected,they were divided into two groups.The treatment group included 67 cases who received the combined therapy with ETV and ADV.The control group included 58 cases who were treated with ETV.The ALT negative rate,HBV-DNA negative rate,HBeAg conversion rate,liver function Child-pugh score conversion rates were compared between the two groups within 12,24,48 weeks.Results After treatment for 12,24,48 weeks,in the treatment group,the ALT negative rates were 65.5％,81.0％,96.6％,respectively,the HBV-DNA negative rates were 62.0％,69.0％,77.6％,respectively,the HBeAg conversion rates were 0.0％,0.0％,17.2％,respectively.The ALT negative rate and HBV-DNA negative rate of the treatment group were higher than those in the control group within 12 and 24 weeks,the differences were statistically significant(ALT negative rate after 12 and 24 weeks,x2 =14.64,8.23;HBV-DNA negative rate after 12 and 24 weeks,x2 =4.57,14.24).The HBeAg conversion rate had no statistically significant difference between the two groups at any time.After treatment for 48 weeks,the Child-pugh score of the treatment group was (6.05 ± 2.11)points,which was significantly lower than (7.67 ± 1.12)points of the control group (t =1.89,P ＜ 0.05).The incidence rate of adverse reactions between the two groups had no statistically significant difference (P ＞ 0.05).Conclusion Entecavir combined with adefovir dipivoxil in the treatment of patients with hepatitis B cirrhosis has good effect on the ALT negative rate,HBV-DNA negative rate.It is worthy of clinical application.

Comparison of efficacy of lamivudine plus adefovir dipivoxil de novo combination therapy with optimization monotherapy in patients with decompensated hepatitis B cirrhosis / 重庆医学

Objective To compare the efficacy of lamivudine (LAM) plus adefovir dipivoxil (ADV) de novo combination therapy to optimization monotherapy for hepatitis B virus-related compensated cirrhosis,and analyze the prediction factors of early response of antivirus treatment.Methods A total of 158 cases of patients with hepatitis B virus-related compensated cirrhosis were selected and randomly assigned to combined group (n=81) and optimized group (n =77) according to randomized digital table.The patients in the combined group accepted LAM combined ADV.The patients in the optimized group were firstly treated with LAM or ADV,then they were given optimized therapy with ADV or LAM if they had poor response or virological breakthrough at week 24.The clinical efficaeies were compared between the two groups,and the prediction factors of early response were analyzed.Results At week 12,the decline level of HBV DNA in the combined group was higher than that in the optimized group (P＜ 0.05),but no statistically significant difference was found in the negative transformation rate of HBV DNA between the two groups (P＞ 0.418).At week 24,the decline level of HBV DNA,rate of undetectable HBV DNA and rate of complete response were higher than those in the optimized group,and rate of virological breakthrough was lower than that in the optimized group (P＜0.05).At week 48,the decline level and negative transformation rate of HBV DNA,negative transformation rate and seroconversion rate of HBeAg were higher than those in the optimized group,and serum levels of hyaluronic acid and a2-macroglobulin were lower than those in the optimized group (P＜0.05).There was no statistically significant difference in the recover rate of alanine aminotransferase (ALT),rate of complete response and rate of virological breakthrough between the two groups at week 48 (P＞0.05).Logistic regression analysis showed that the complete response at week 24 was correlated with HBV DNA load,expression of HBeAg,level of ALT and initial treatment (P＜0.05).Layered evaluation showed that the rate of early complete response in the combined group was significantly higher than that in the optimized group,regardless of HBV DNA load,expression of HBeAg,and level of ALT (P＜0.05).Conclusion LAM combined with ADV can reduce resistance and improve the rate of early complete response,which has stronger antiviral activity.In addition,it can improve the liver function and partially reverse cirrhosis.

Therapeutic Efficacy of Lamivudine Combined with Adefovir Dipivoxil in the Treatment of Lamivudine-re-sistant Chronic Hepatitis B Patients and Its Relationship with HBV Genotype / 中国药房

OBJECTIVE:To evaluate therapeutic efficacy of lamivudine(LAM)combined with adefovir dipivoxil(ADV) in the treatment of LAM-resistant chronic hepatitis B patients,and to study the relationship of therapeutic efficacy with hepatitis B virus(HBV)genotype. METHODS:A total of 101 LAM-resistant chronic hepatitis B patients selected during Dec. 2012 to Dec. 2014 were given LAM+ADV for 24 months at least. Regular outpatient visits or telephone follow-up were also performed. Polymerase chain reaction-reverse dot blot method was used to determine the HBV genotype. Chi-square test,Kaplan-Meier meth-od and Log-rank test were used to compare the virological response(HBV-DNA clearance rate)and biological response(ALT normalization rate and HBeAg seroconversion rate)among different genotypes at the 6th,12th,18th and 24th month of fol-low-up. RESULTS:The follow-up rate was 100%,without missed follow-up. Two genotypes were detected,including 34 pa-tients(33.7%)with genotype B and 67 patients(66.3%)with genotype C.At each time point mentioned above,the HBV-DNA clearance rates of 101 patients were 34.7%,55.4%,79.2% and 93.1%.At 6th month,HBV-DNA clearance rate and accumula-tive HBV-DNA clearance rate of genotype B were significantly higher than genotype C,with statistical significance(P<0.05). There was no statistical significance in HBV-DNA clearance rates or accumulative HBV-DNA clearance rates between different genotypes at other time points(P>0.05). At each time point mentioned above,ALT normalization rates of 101 patients were 40.6%,69.3%,82.2%,84.2%;there was no statistical significance in ALT normalization rates or accumulative ALT normaliza-tion rates between different genotypes(P>0.05). At each time point mentioned above,the HBeAg seroconversion rates of 101 patients were 10.9%,19.8%,24.8%,29.7%;there was no statistical significance in the HBeAg seroconversion rates or accu-mulative HBeAg seroconversion rates between different genotypes(P>0.05). CONCLUSIONS:LAM combined with ADV is ef-fective for LAM-resistant chronic hepatitis B patients. Moreover,the combination therapy can achieve earlier viological response in patients with genotype B than those with genotype C.

Clinical study of entecavir and adefovir dipivoxil in the treatment of decompensated cirrhosis of hepatitis B / 中国生化药物杂志

Objective To investigate the clinical efficacy of entecavir and adefovir dipivoxil in the treatment of decompensated cirrhosis with hepatitis B virus. Methods 100 cases of decompensated cirrhosis of hepatitis B in our hospital (February 2015 to October 2016) were randomly divided into control group and experimental group, each with 50 cases. The control group was treated with adefovir dipivoxil, and the experimental group was treated with entecavir and adefovir dipivoxil. The clinical symptoms of the two groups were compared and analyzed. Results After treatment, the level of ALT in the experimental group was (46.20±3.21) U/L, and the level of AST was (52.40±3.90) U/L.The level of ALT in the control group was (70.43±10.90) U/L, and the level of AST was (70.33±9.19)U/L, and the two groups had statistical significance (P＜0.05). The negative rate of HBV-DNA in the experimental group was 76.0%, which was significantly higher than that in the control group (58.0%), and there was statistical difference (P＜0.05). The negative rate of HBeAg in the two groups was 22.0% and 24.0% respectively, and there was no significant difference. Conclusion Entecavir and adefovir dipivoxil in the treatment of hepatitis B liver cirrhosis patients clinical effect is ideal,can significantly improve the liver function, improve clinical symptoms, high safety, has clinical significance.