Effects of nucleos(t)ide analogs on hepatitis B surface antigen reduction with interferon-lambda 3 induction in chronic hepatitis B patients.

BACKGROUND & AIMS: Benefits of nucleos(t)ide analogs (NAs) on hepatitis B surface antigen (HBsAg) reduction and interferon-lambda3 (IFN-λ3) induction are still not known. This study aimed to investigate the effects of NAs on HBsAg reduction and association with serum IFN-λ3 levels in chronic hepatitis B (CHB) patients. METHODS: A total of 91 patients [51 treated with nucleoside analog entecavir hydrate (ETV) and 40 treated with nucleotide analog adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF)] with clinically evident CHB (chronic hepatitis, 57; liver cirrhosis, 34) were enrolled in this study. Serum IFN-λ3 levels among patients receiving ETV and ADV/TDF were measured before the initiation of therapy and 1, 3, and 5 years post-therapy. RESULTS: The change (mean ± standard deviation) in serum HBsAg levels from baseline to year five was -0.38 ± 0.46 and -0.84 ± 0.64 log10 IU/ml in ETV and ADV/TDF groups, respectively (p = 0.0004). Higher serum IFN-λ3 levels were observed in ADV/TDF group compared with ETV group during treatment (p < 0.001). Serum IFN-λ3 levels showed negative correlation with HBsAg reduction in ADV/TDF group (r = -0.386, p = 0.038) at week 48. Nucleotide analogs (ADV/TDF) treatment has associated factors with -0.3 log HBsAg decline at 1 year, -0.5 log HBsAg decline at 3 years, and -0.8 log HBsAg decline at 5 years after NAs treatment on multivariate analysis. CONCLUSIONS: Nucleotide analog (ADV/TDF) treatment reduced HBsAg levels greater compared with nucleoside analog (ETV) in parallel with IFN-λ3 induction.

Renal safety and biochemical changes for 2 years after switching to tenofovir alafenamide from long-term other nucleotide analog treatment in patients with chronic hepatitis B.

BACKGROUND: Long-term use of nucleotide analogs such as adefovir (ADV) or tenofovir disoproxil fumarate (TDF) may cause renal impairment. Tenofovir alafenamide (TAF) has less systemic exposure than TDF did. The aims were to examine longitudinal changes in renal function and biochemical parameters for 2 years after switching from long-term ADV and TDF to TAF, and to explore factors associated with improved renal function after TAF in patients with chronic hepatitis B. METHODS: The prospective observational cohort study included 306 patients with chronic hepatitis B who underwent switching from long-term TDF or ADV to TAF. The primary outcome was the changes in estimated glomerular filtration rate (eGFR) after TAF. RESULTS: Among 306 patients, 190 (65.3%) and 106 (34.7%) had chronic kidney disease (CKD) stages 1-2 and 3a-4 at baseline. In patients with CKD stages 3a-4, the mean eGFR significantly increased until week 12 and plateaued from week 12 to year 2 (adjusted slope using linear mixed effect models: +9.01 ml/min/1.73 m2 /year until week 12; p < 0.001). In contrast, the mean eGFR plateaued from baseline to year 2 in the CKD stages 1-2 subgroup. Multivariate logistic regression showed that baseline CKD stage ≥3a, steeper decline in eGFR 1 year before TAF, and shorter duration of any nucleotide analog use was significantly associated with ≥10% improvement in eGFR in year 1. CONCLUSIONS: Switching from TDF or ADV to TAF resulted in favorable renal safety for 2 years. In CKD stage 3a-4 subgroup, eGFR after TAF was recovered in the first 12 weeks and subsequently stabilized.

Effect of Coformer Selection on In Vitro and In Vivo Performance of Adefovir Dipivoxil Cocrystals.

PURPOSE: This study aimed to improve the in vitro dissolution, permeability and oral bioavailability of adefovir dipivoxil (ADD) by cocrystal technology and clarify the important role of coformer selection on the cocrystal's properties. METHODS: ADD was cocrystallized with three small molecules (i.e., paracetamol (PA), saccharin (SAC) and nicotinamide (NIC)), respectively. The obtained ADD-PA cocrystal was characterized by DSC, TGA, PXRD and FTIR. Comparative study on dissolution rates among the three ADD cocrystals were conducted in water and pH 6.8 phosphate buffer. Besides, effects of coformers on intestinal permeability of ADD were evaluated via in vitro Caco-2 cell model and in situ single-pass intestinal perfusion model in rats. Furthermore, in vivo pharmacokinetic study of ADD cocrystals was also compared. RESULTS: Dissolution rates of ADD cocrystals were improved with the order of ADD-SAC cocrystal > ADD-PA cocrystal > ADD-NIC cocrystal. The permeability studies on Caco-2 cell model and single-pass intestinal perfusion model indicated that PA could enhance intestinal absorption of ADD by P-gp inhibition, while SAC and NIC did not. Further in vivo pharmacokinetic study showed that ADD-SAC cocrystal exhibited higher Cmax (1.4-fold) and AUC0-t (1.3-fold) of ADD than administration of ADD alone, and Cmax and AUC0-t of ADD-PA cocrystal were significantly enhanced by 2.1-fold and 2.2-fold, respectively, which was attributed to its higher dissolution and improved intestinal permeability. CONCLUSION: Coformer selection had an important role on cocrystal's properties, and cocrystallization of ADD with a suitable coformer was an effective approach to enhance both dissolution and bioavailability of ADD.

Transforming growth factor ß (TGFß) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation.

Transforming growth factor ß (TGFß) potently activates hepatic stellate cells (HSCs), which promotes production and secretion of extracellular matrix (ECM) proteins and hepatic fibrogenesis. Increased ECM synthesis and secretion in response to TGFß is associated with endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). TGFß and UPR signaling pathways are tightly intertwined during HSC activation, but the regulatory mechanism that connects these two pathways is poorly understood. Here, we found that TGFß treatment of immortalized HSCs (i.e. LX-2 cells) induces phosphorylation of the UPR sensor inositol-requiring enzyme 1α (IRE1α) in a SMAD2/3-procollagen I-dependent manner. We further show that IRE1α mediates HSC activation downstream of TGFß and that its role depends on activation of a signaling cascade involving apoptosis signaling kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK). ASK1-JNK signaling promoted phosphorylation of the UPR-associated transcription factor CCAAT/enhancer binding protein ß (C/EBPß), which is crucial for TGFß- or IRE1α-mediated LX-2 activation. Pharmacological inhibition of C/EBPß expression with the antiviral drug adefovir dipivoxil attenuated TGFß-mediated activation of LX-2 or primary rat HSCs in vitro and hepatic fibrogenesis in vivo Finally, we identified a critical relationship between C/EBPß and the transcriptional regulator p300 during HSC activation. p300 knockdown disrupted TGFß- or UPR-induced HSC activation, and pharmacological inhibition of the C/EBPß-p300 complex decreased TGFß-induced HSC activation. These results indicate that TGFß-induced IRE1α signaling is critical for HSC activation through a C/EBPß-p300-dependent mechanism and suggest C/EBPß as a druggable target for managing fibrosis.

Adefovir dipivoxil induces DNA replication stress and augments ATR inhibitor-related cytotoxicity.

Replication stress is a common feature of cancer cells. Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) signalling, a DNA damage repair (DDR) pathway, is activated by regions of single-stranded DNA (ssDNA) that can arise during replication stress. ATR delays cell cycle progression and prevents DNA replication fork collapse, which prohibits cell death and promotes proliferation. Several ATR inhibitors have been developed in order to restrain this protective mechanism in tumours. It is known, however, that despite other effective anticancer chemotherapy treatments targeting DDR pathways, resistance occurs. This begets the need to identify combination treatments to overcome resistance and prevent tumour cell growth. We conducted a drug screen to identify potential synergistic combination treatments by screening an ATR inhibitor (VE822) together with compounds from a bioactive small molecule library. The screen identified adefovir dipivoxil, a reverse transcriptase inhibitor and nucleoside analogue, as a compound that has increased cytotoxicity in the presence of ATR, but not ATM or DNA-dependant protein kinase (DNA-PK) inhibition. Here we demonstrate that adefovir dipivoxil induces DNA replication stress, activates ATR signalling and stalls cells in S phase. This simultaneous induction of replication stress and inhibition of ATR signalling lead to a marked increase in pan-nuclear γH2AX-positive cells, ssDNA accumulation and cell death, indicative of replication catastrophe.

Retrospective analysis of the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population.

WHAT IS KNOWN AND OBJECTIVE: To explore the clinical characteristics of adefovir dipivoxil-induced Fanconi's syndrome in the Chinese population and provide a reference for rational drug use in the clinic. METHODS: By searching the CNKI, Wanfang, Chinese VIP, PubMed/MEDLINE, Web of Knowledge, Ovid, Elsevier and SpringerLink databases during 1 January 2008 to 31 December 2019, 78 studies of ADV-induced Fanconi's syndrome involving a total of 110 patients were collected and analysed retrospectively. RESULTS AND DISCUSSION: Prolonged usage of adefovir dipivoxil at low doses to treat hepatitis B might cause Fanconi's syndrome as the first symptom, especially for use over 12 months.The main clinical manifestation was bone pain accompanied by hypophosphataemia, elevated alkaline phosphatase (ALP), urine glycosuria and urine protein. X-rays and bone mineral density (BMD) examinations were mainly used to characterized osteoporosis. The patients had pain relief within 1 week to 1 month, and the biochemical indicators returned to normal within from 2 to 4 months. WHAT IS NEW AND CONCLUSION: Sufficient attention is required before and during exposure to long-term ADV therapy. The clinical picture, laboratory and radiograph alterations are important clues for ADV-induced Fanconi's syndrome.

Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial.

BACKGROUND & AIMS: Tenofovir disoproxil fumarate (TDF) monotherapy has displayed non-inferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to ETV and/or adefovir (ADV). Nonetheless, the virologic response rate was suboptimal in patients receiving up to 144 weeks of TDF monotherapy. We aimed to assess the efficacy and safety of TDF monotherapy given for up to 240 weeks. METHODS: One trial enrolled patients with ETV resistance without ADV resistance (n = 90), and another trial included patients with ADV resistance (n = 102). Most patients (91.2%) also had lamivudine resistance. Patients were randomized 1:1 to receive TDF monotherapy or TDF + ETV combination therapy for 48 weeks, and then TDF monotherapy until week 240. We compared efficacy between the studies and safety in the pooled population at 240 weeks. RESULTS: At week 240, the proportion of patients with serum HBV DNA <15 IU/ml was not significantly different between the ETV and ADV resistance groups in the full analysis set (84.4% vs. 73.5%; p = 0.07), which was significantly different by on-treatment analysis (92.7% vs. 79.8%; p = 0.02). Virologic blips associated with poor medication adherence occurred in 7 patients throughout the 240 weeks. None developed additional HBV resistance mutations. Among the 170 HBV e antigen (HBeAg)-positive patients at baseline, 12 (7.1%) achieved HBeAg seroconversion at week 240. None achieved HBV surface antigen seroclearance. Significant decreases from baseline were observed at week 240 in the estimated glomerular filtration rate (-3.21 ml/min/1.73 m2 by the CKD-EPI equation, p <0.001) and bone mineral density (g/cm2) at the femur (-2.48%, p <0.001). CONCLUSIONS: Up to 240 weeks of TDF monotherapy provided an increasing virologic response rate in heavily pretreated patients with HBV resistant to ETV and/or ADV. However, it was associated with poor serological responses and decreasing renal function and bone mineral density. (ClinicalTrials.gov No, NCT01639066 and NCT01639092). LAY SUMMARY: In patients chronically infected with hepatitis B virus resistant to multiple drugs including lamivudine, entecavir, and/or adefovir, tenofovir disoproxil fumarate (TDF) monotherapy showed non-inferior efficacy compared with the combination therapy of TDF plus entecavir. Nonetheless, short-term TDF monotherapy was associated with suboptimal virologic response, and its long-term safety was uncertain. This study displayed that 240 weeks of TDF monotherapy provided a virologic response in most of those patients, but it was associated with poor serological responses and decreasing renal function and bone mineral density.

Neutrophil gelatinase-associated lipocalin accurately predicts renal tubular injury in patients with chronic hepatitis B treated with nucleos(t)ide analogs.

AIM: Little is known about the impact of long-term use of nucleos(t)ide analogs on tubular function in patients with chronic hepatitis B. Previous studies showed that neutrophil gelatinase-associated lipocalin (NGAL) elevation was associated with renal tubular injury. We evaluated renal function markers and bone mineral density in patients treated long-term with adefovir dipivoxil (ADV) or entecavir (ETV). METHODS: In this cross-sectional study, we enrolled 78 patients (ADV, 36; ETV: 42), and 21 patients matched for age, observation time, and baseline estimated glomerular filtration rate from each group. RESULTS: Patients treated with ADV showed a significant increase in serum creatinine and urine ß2 -microglobulin, and decreased estimated glomerular filtration rate and bone mineral density. Furthermore, the median levels of NGAL in patients treated with ADV were significantly higher than those of ETV (12.5 ng/mL vs. 2.5 ng/mL, P = 0.020). The proportions of patients with proteinuria and phosphate <1 mmol/L in the ADV group were higher than those in the ETV group. Additionally, age, ß2 -microglobulin, phosphate, and ADV use were associated with altered NGAL levels on multivariate analysis. Among the commonly used biomarkers, NGAL was the most useful (odds ratio = 5.72; P = 0.005) and specific (92% specificity at 18.1 ng/mL cut-off) in predicting low bone mass. CONCLUSIONS: Patients with chronic hepatitis B treated long-term with ADV showed elevated urinary NGAL levels. Neutrophil gelatinase-associated lipocalin was more specific in predicting low bone mass during therapy compared with ß2 -microglobulin, phosphate, and creatinine. In general, this analysis examined the value of NGAL as a renal tubular injury indicator, resulting from ADV use.

Adefovir dipivoxil loaded proliposomal powders with improved hepatoprotective activity: formulation, optimization, pharmacokinetic, and biodistribution studies.

The present study aimed to prepare proliposomal formulae for improving the oral bioavailability of adefovir dipivoxil (AD), a nucleoside reverse transcriptase inhibitor effective against hepatitis B virus (HBV). The prepared proliposomal formulae were characterized for entrapment efficiency (E.E.%), vesicle size and in vitro drug release after reconstitution to conventional liposomes. The optimized formula (F9) with a maximum desirability value of 0.858 was selected having E.E.% of 71 ± 3.3% with an average vesicle size of 164.6 ± 5 nm. Moreover, the crystallization of AD within the optimized formula investigated via powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) confirmed the presence of the drug in an amorphous state within the lipid vesicles with enhanced stability over a storage period of 12 months. Thioacetamide-induced liver damage in rats evidenced by elevated liver enzymes was significantly improved after treatment with the optimum formula. Pharmacokinetic and biodistribution studies of formula F9 showed a higher accumulation of AD in the liver with enhanced bioavailability compared to AD suspension which highlights its potential advantage for an effective treatment of chronic HBV. Hence, proliposomal drug delivery is considered as a better choice for the oral delivery of AD.

Preparation and characterization of adefovir dipivoxil-stearic acid cocrystal with enhanced physicochemical properties.

The objectives of this study were to prepare cocrystal composed of adefovir dipivoxil (AD) and stearic acid (SA) and to investigate the enhanced properties of the cocrystal. The cocrystal was prepared by antisolvent precipitation and characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC). The enhanced properties were evaluated by dissolution testing, permeability studies, and powder rheology analysis. The AD raw material has a cuboid-like crystal and the cocrystal has a needle shape. In the FT-IR study, there were bathochromic shifts caused by the hydrogen bonding. The melting point of the cocrystal was 52.9 °C, which was lower than that of AD. The XRPD pattern also had distinct differences, supporting the formation of a new crystalline form. The cocrystal showed changes in the lattice energy and the solvation strength, which caused an enhanced dissolution. The permeability was increased due to the SA, which acts as a P-gp inhibitor. The tabletability was enhanced due to the altered crystal habit. In conclusion, cocrystal containing AD and SA was successfully prepared, presenting advantages such as enhanced solubility, tabletability, and permeability. The use of the cocrystal is a desirable approach for the improved physicochemical properties.

[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].

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 m(2))(-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.

Variability in long-term hepatitis B virus dynamics under antiviral therapy.

Hepatitis B virus (HBV) dynamics in treated patients can be complex and differ considerably from other viral infections. We analyse dynamics of liver and serum levels of HBV DNA in 24 chronically HBV-infected individuals undergoing 1 year of combination therapy with pegylated interferon alpha and adefovir dipivoxil (ADV), followed by 2 years of ADV monotherapy. Serum viral dynamics differentiated the patients into four response groups dependent on how quickly viremia became undetectable: quickly suppressed (HBV DNA <100 copies/ml within 8 weeks and staying suppressed, GRP1); quickly suppressed but some rebound (<10,000 copies/ml, GRP2); slow decay (GRP3); virological failures (>10,000 copies/ml, GRP4). These groups did not differ before start of therapy by serum HBV DNA (p=0.2), HBsAg (p=0.1), ALT (p=0.4), total HBV DNA within the liver (p=0.08), or cccDNA (p=0.3). Despite very different serum HBV DNA levels after 3 years, there was no statistical difference in total HBV DNA within the liver (p=0.08), nor in cccDNA levels (p=0.1), but HBsAg levels in serum were significantly lower for GRP1 compared to GRP4 (p=0.02). Efficacy in terms of reduction over the 3 years of serum HBV DNA, liver HBV DNA, cccDNA, and ratios of liver HBV DNA to cccDNA were 99.98%, 99.5%, 98.4%, and 83.2% respectively, exhibiting larger antiviral effects in serum than in liver. Over the course of therapy, HBV DNA viremia exhibited large oscillations for some individuals. Mathematical modelling reproduced the dynamics of these diverse groups by assuming a number of viral clones arose that experienced delayed recognition by the antibody response. Large viremia oscillations under therapy suggest sequential outgrowth of viral clones with delayed recognition by the humoral response.

De novo entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations resulting from sequential therapy with adefovir dipivoxil, and lamivudine.

BACKGROUND: Entecavir-resistance mutations are commonly induced by entecavir treatment in chronic hepatitis B patients. However, entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations induced by sequential or combination treatment with lamivudine and adefovir dipivoxil have never been reported. RESULTS: We retrospectively reviewed 1200 patients who had been tested for anti-HBV drug resistance at Beijing Ditan Hospital of Capital Medical University, and five patients showing multidrug resistance to lamivudine and adefovir dipivoxil were enrolled. Stored serum samples were used for genetic analysis, which yielded a total of 135 clones. Entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations were identified in 60 % (3/5) entecavir-naïve patients who received sequential therapy with adefovir dipivoxil and lamivudine. Specifically, we found one rtM204I+rtL180 M+rtM250 V+rtA181 V clone among 23 clones from patient 1 (4.35 %), one rtM204 V+vrtL180 M +rtM250 V+rtA181 V clone among 24 clones from patient 2 (4.17 %), and 2 clones harboring rtM204 V+rtL180 M+rtM250 V+rtA181 V and rtM204 V+rtL180 M+rtI169 V+rtA181 V among 20 clones from patient 3 (10.0 %). The other 2 patients showed multidrug resistance after lamivudine/telbivudine and adefovir dipivoxil combination therapy, but no entecavir-resistance mutations were found in these two patients. CONCLUSION: De novo entecavir+adefovir dipivoxil+lamivudine triple-resistance mutations can be induced by sequential therapy with adefovir dipivoxil and lamivudine in patients who never take entecavir. These results provide important information for sequential therapy with adefovir dipivoxil and lamivudine and the use of entecavir as a rescue therapy for these patients with multidrug resistance.

The rtA181S mutation of hepatitis B virus primarily confers resistance to adefovir dipivoxil.

The study aimed to clarify clinical significance of hepatitis B virus (HBV) rtA181S mutation in Chinese HBV-infected patients. A total of 18 419 patients with chronic HBV infection from Beijing 302 Hospital were investigated. HBV complete reverse transcriptase region of polymerase was screened by direct sequencing, and the results were verified by clonal sequencing. Replication-competent mutant and wild-type HBV genomic amplicons were constructed and transfected into the HepG2 cells and cultured in the presence or absence of serially diluted nucleos(t)ide analogues. Intracellular HBV replicative intermediates were quantitated for calculating the 50% effective concentration of the drug (EC(50)). The rtA181S was detected in 98 patients with 12 kinds of mutational patterns. Genotype C and genotype B HBV infection occupied 91.8% and 8.2% in rtA181S-positive patients, in contrast to 84.6% and 15.4% in rtA181S-negative patients (P < 0.01). All rtA181S-positive patients had received nucleos(t)ide analogues. rtA181S was detected in multiple patients with virologic breakthrough. Phenotypic analysis of patient-derived viral strains showed that rtA181S, rtA181S+N236T, rtN236T and rtA181V strains had 68.5%, 49.9%, 71.4% and 66.2% of natural replication capacity of wild-type strain, and 3.7-fold, 9.8-fold, 7.9-fold and 5.6-fold increased EC(50) to adefovir dipivoxil (ADV). The rtA181S strain remained susceptible to lamivudine, entecavir and tenofovir, and ADV susceptibility was restored after the mutation was eliminated through site-directed mutagenesis. Rescue therapy with entecavir or combination therapy was effective in rtA181S-related ADV-refractory patients. The rtA181S mutation confers moderate resistance to ADV. It could be induced by either lamivudine or ADV and contribute ADV treatment failure.

Randomized, three-arm study to optimize lamivudine efficacy in hepatitis B e antigen-positive chronic hepatitis B patients.

BACKGROUND AND AIM: Data about the efficacy of de novo combination therapies, or optimization strategy by adding the other drug based on the virological response at week 24 of low genetic barrier antiviral agents is still limited. This study aimed to compare the efficacy at week 104 of lamivudine monotherapy (MONO), lamivudine plus adefovir dipivoxil (ADV) combination therapy (COMBO), and lamivudine optimization strategy (OPTIMIZE). METHODS: Adult patients without antiviral therapy within 6 months before screening with hepatitis B virus (HBV)-DNA ≥ 10(5) copies/mL, alanine aminotransferase 1.3-10 times upper limit of normal and compensated hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were randomized into three groups with 1:1:1 ratio. Patients in OPTIMIZE group started with lamivudine 100 mg q.d., and ADV 10 mg q.d. was added to suboptimal responders (HBV-DNA > 1000 copies/mL at week 24) from week 30 to week 104, whereas patients with early virological response (HBV-DNA ≤ 1000 copies/mL at week 24) continued MONO until week 104. For all the patients receiving MONO, ADV would be added if virological breakthrough was confirmed. RESULTS: At week 104, more patients in COMBO and OPTIMIZE groups achieved HBV-DNA < 300 copies/mL (53.3% [64/120] and 48.3% [58/120]), with less lamivudine resistance (0.8% and 6.7%) compared with MONO group (HBV-DNA < 300 copies/mL 34.8% [41/118], lamivudine resistance 58.5%). Patients under MONO with early virological response showed superior efficacy at week 104 (HBV-DNA < 300 copies/mL 73.1% [38/52], HBeAg seroconversion 40.4% [21/52]). All regimens were well tolerated. CONCLUSION: Combination therapy of lamivudine plus ADV exhibited effective viral suppression and relatively low resistance in HBeAg-positive CHB patients. In lamivudine-treated patients with suboptimal virological response at week 24, promptly adding on ADV is necessary to prevent resistance development.

Osteomalacia and Fanconi's syndrome caused by long-term low-dose adefovir dipivoxil.

WHAT IS KNOWN AND OBJECTIVE: Adefovir dipivoxil (ADV) is recommended for patients infected with lamivudine-refractory hepatitis B virus (HBV). We report a case of low-dose ADV-induced hypophosphatemic osteomalacia that initially presented as diffuse musculoskeletal pain. CASE SUMMARY: A 59-year-old Chinese man reported an 18-month history of severe chest wall pain and multiple bone pain during the previous 4 months with no antecedent trauma. There was no clinical evidence of an infectious, inflammatory or malignant process. Medical history showed that the patient had a history of chronic hepatitis B infection, and receiving lamivudine at a daily dose of 100 mg for 70 months. Lamivudine was changed to adefovir (10 mg/day) for the past 42 months. His serum inorganic phosphorus concentration was significantly low (0·4 mmol/l; 0·81-1·5 mmol/L), and the result of a urine routine test was abnormal. Combined with unbearable bone pain, spontaneous fractures, changes in laboratory markers and the result of ECT and other radiographic findings, the diagnosis of Fanconi's syndrome with osteomalacia was established. Dramatic clinical, laboratory and imaging improvement was observed after ADV discontinuation. WHATS IS NEW AND CONCLUSION: This case indicates that Fanconi's syndrome with osteomalacia can be acquired by a chronic hepatitis B patient taking ADV at a conventional dosage of 10 mg/day. Therefore, patients with HBV treated with long-term ADV should be regularly monitored for renal function, serum calcium and serum phosphate. Urine testing for ion concentration should also be undertaken.

Relationship Between Serum DNA Replication, Clinicopathological Characteristics and Prognosis of Hepatitis B Virus-associated Glomerulonephritis with Severe Proteinuria by Lamivudine Plus Adefovir Dipivoxil Combination Therapy.

OBJECTIVE: To explore the relationship between HBV DNA and the clinical manifestations, pathological types, injury severity, and prognosis with HBV-GN. METHODS: 102 patients with HBV-GN were divided into 3 groups, according to the serum titer of the HBV DNA. 24-h urine protein excretion, and other parameters were measured. Renal biopsy were performed. The association between HBV DNA and the pathological stage of membranous nephropathy was analyzed in 78 patients with HBV-MN. 24-h urine protein excretion was used for the evaluation of the prognosis, and the relationship between HBV DNA and prognosis were analyzed. RESULTS: Several findings were demonstrated with the increase of serum HBV DNA: 24-h urine protein excretion, plasma cholesterol, and triglycerides increased significantly (P%lt;0.05), while the plasma level of albumin decreased significantly (P%lt;0.05); The changes of serum creatinine, C3 and C4 were found but no statistical significance. Glomerular deposition of HBVAg increased, and the pathological injury was more severe. The clinical remission rate was lower in the high replication group after treatment as compared with the low replication group (P%lt;0.01). CONCLUSION: With the increase of serum HBV DNA, the urine protein excretion and the kidney injury were more severe, and the clinical remission rate was decreased.

Combination therapy of interferon and nucleotide/nucleoside analogues for chronic hepatitis B.

Chronic hepatitis B is one of the leading causes of cirrhosis and hepatocellular carcinoma globally. At present, seven drugs, including two interferons and five oral nucleos(t)ide analogues (NAs), have been approved for the treatment of chronic hepatitis B. Interferon works by immunomodulation, but is successful in less than a third of treated patients and is a relatively weak antiviral. NAs directly suppress the hepatitis B virus but have limited durability. Based on current data, combination of NA and interferon results in greater viral suppression but does not translate to off-treatment sustained response. Concomitant or sequential treatment also does not make a difference. Combining telbivudine and interferon also runs the risk of severe peripheral neuropathy. On the other hand, interferon switch or additional therapy in patients well controlled with NAs appears to improve the durability of off-treatment response. This article reviews current data on interferon and NA combination and discusses potential future developments.

Telbivudine protects renal function in patients with chronic hepatitis B infection in conjunction with adefovir-based combination therapy.

Previous studies have demonstrated that the treatment of chronic hepatitis B (CHB) infection with adefovir (ADV) can impair renal function. In contrast, treatment with telbivudine (LdT) improves renal function in CHB patients. The aim of this study was to evaluate the renoprotective effect of LdT in CHB patients receiving ADV-based combination therapy. The effects of treatment with ADV + LdT on renal function were compared to those resulting from treatment with ADV + entecavir (ETV), ADV + lamivudine (LAM), ADV alone and ETV alone. The consecutive cohort analysis included 831 CHB patients who received ADV + LdT, ADV + LAM, ADV + ETV, ADV alone or ETV alone for 96 weeks. Alterations in estimated glomerular filtration rate (eGFR) were compared between the five groups using a linear mixed-effects model. HBV DNA levels were also compared between the five groups during the 96-week period. Among the five treatment groups, significant improvements in eGFR were observed in the ADV + LdT and ADV + LAM groups over time (P < 0.001 for each group compared with baseline eGFR). In patients with a baseline eGFR between 50 and 90 mL/min, the change in eGFR was the most significant in the ADV + LdT group (+0.641 mL/min; P < 0.001). Age, gender, baseline eGFR and treatment option were significant predictive factors for eGFR changes. In conclusion, our results suggest that the combination therapy of LdT and ADV is significantly associated with renoprotective effects in CHB patients when compared with other ADV-based combination or single therapies.

De novo combination therapy adefovir plus lamivudine as a treatment for women of child-bearing age with HBeAg-positive chronic hepatitis B before pregnancy.

Substantial progress has been achieved in antiviral therapy for chronic hepatitis B; however, options for women of child-bearing age with HBeAg-positive chronic hepatitis B remain a challenge. In this study, we sought to determine whether de novo combination therapy of Adefovir plus Lamivudine was a super treatment for women of child-bearing age with HBeAg-positive chronic hepatitis B prior to conception. A total of 122 women patients of child-bearing age with HBeAg-positive chronic hepatitis B were randomly assigned to receive (i) 10 mg Adefovir plus 100 mg Lamivudine (64 patients) or (ii) 10 mg Adefovir monotherapy (58 patients), administrated orally once daily for 96 weeks. The therapeutic efficacy within each group was compared at weeks 48 and 96. The results showed that de novo combination therapy of Adefovir plus Lamivudine significantly reduced HBV-DNA detectability, and enhanced ALT normalization and HBeAg seroconversion in women of child-bearing age with HBeAg-positive chronic hepatitis B. No virological breakthrough and genotypic resistance were observed in the combination therapy group. Additionally, the combination therapy with Adefovir plus Lamivudine was well tolerated. This study suggests that de novo combination therapy of Adefovir plus Lamivudine offers a therapeutic advantage for women of child-bearing age with HBeAg-positive chronic hepatitis B when taken before conception.