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Frontiers in Pharmacology 2021Adefovir dipivoxil (ADV) is widely used for chronic hepatitis B therapy in China. To explore the clinical features and prognosis of ADV-induced osteomalacia and to...
Adefovir dipivoxil (ADV) is widely used for chronic hepatitis B therapy in China. To explore the clinical features and prognosis of ADV-induced osteomalacia and to analyze the association between osteomalacia and genetic variants in 51 drug transporters genes. Clinical and follow-up data of the ADV-treated patients were collected. Target capture sequencing was used to identify genetic variations of 51 drug transporter genes. A total of 193 hepatitis B patients treated with ADV were enrolled, of whom 140 had osteomalacia. The other 53 without osteomalacia were included in the control group. The median duration of ADV treatment before the onset of osteomalacia was 6.5 years (range:1.5-7 years). We found that most patients with osteomalacia had hypophosphatemia, high serum alkaline phosphatase levels, hypouricemia, nondiabetic glycosuria, proteinuria. Stopping ADV administration, supplementing calcitriol and calcium were effective treatments. During 3-6 months of follow-up, the clinical symptoms and biochemical indicators of patients with osteomalacia have been significantly improved. There was no significant difference in duration of adefovir treatment in patients with or without osteomalacia ( = 0.791). Through regression analysis, we found that age was a risk factor for osteomalacia [per 1 year, odds ratio (OR), 1.053; 95% confidence interval (95% CI), 1.020-1.087; = 0.015]. 1992 single nucleotide variants were found using target capture sequencing. However, the associations of genetic variants of 51 drug transporter genes and the risk of osteomalacia were negligible. Osteomalacia is prone to occur in patients with chronic hepatitis B treated with long-term ADV at a therapeutic dose. After standard treatment, the prognosis is mostly good. We failed to find genetic variants that can predict the risk of ADV-induced osteomalacia.
PubMed: 33995038
DOI: 10.3389/fphar.2021.636352 -
Scientific Reports Feb 2020Our study purpose was to evaluate mitochondrial (mt)DNA and RNA in peripheral blood mononuclear cells (PBMCs) and body shape changes (BSC) in HBV-infected patients.... (Clinical Trial)
Clinical Trial
Our study purpose was to evaluate mitochondrial (mt)DNA and RNA in peripheral blood mononuclear cells (PBMCs) and body shape changes (BSC) in HBV-infected patients. mtDNA and mtRNA were measured in PBMCs. The presence of BSC was evaluated through a questionnaire and clinical evaluation. A total of 157 subjects were enrolled, of these 107 were HBV-infected patients, 54 receiving nucleoside analogues (NAs, Group A), 53 naive to antivirals (Group B) and 50 age-sex matched controls (Group C). All HBV-treated patients had negative HBV-DNA. Twenty (37,0%) received lamivudine + adefovir, 20 (37.0%) tenofovir, 2 (3.7%) lamivudine and 12 (22.2%) entecavir. Therapy median duration was 38 months (IQR 20-60) in NA-treated patients. Group A showed significantly higher mtDNA/nuclear (n) DNA ratio (p = 0.000008) compared to Group C and Group B (p = 0.002). Group B showed significantly higher mtDNA/nDNA ratio compared to Group C (p = 0.017). Group A and B had significantly lower mtRNA/nRNA ratio compared to Group C (p = 0.00003 and p = 0.00006, respectively). Tenofovir and entecavir showed less impact compared to lamivudine + adefovir. mtDNA/nDNA ratio positively (Rho = 0.34, p < 0.05) and mtRNA/nRNA ratio negatively (Rho = -0.34, p < 0.05) correlated with therapy duration. BSC were significantly more frequent in Group A [10/54 (18.5%)] compared to Group B [3/53 (5.6%, p = 0.04)] and Group C [0/50, (p = 0.0009)]. In conclusion, long-term NA therapy was associated both to mitochondrial toxicity and BSC, showing significant differences in mtDNA and mtRNA levels. Tenofovir and entecavir showed lower impact on alterations, compared to 1 generation NA.
Topics: Adenine; Adiposity; Antiviral Agents; Cross-Sectional Studies; DNA, Mitochondrial; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Female; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Leukocytes, Mononuclear; Male; Middle Aged; Mitochondria; Organophosphonates; RNA, Mitochondrial; Tenofovir
PubMed: 32029790
DOI: 10.1038/s41598-020-58837-3 -
Analytical Biochemistry May 2020Although the unique mechanism by which hepatitis B virus (HBV) polymerase primes reverse transcription is now well-characterized, the subsequent elongation process...
Although the unique mechanism by which hepatitis B virus (HBV) polymerase primes reverse transcription is now well-characterized, the subsequent elongation process remains poorly understood. Reverse transcriptase (RT)-RNase H sequences from polymerase amino acid 304 (the C-terminal part of spacer domain) to 843 were expressed in Escherichia coli and purified partially. RT elongation activity was investigated using the fluorescent-tagged primer and homopolymeric RNA templates. RT elongation activity depended on both Mg and Mn, and had low affinity for purine deoxynucleotides, which may be related with the success of adefovir, tenofovir, and entecavir. However, the polymerization rate was lower than that of human immunodeficiency virus RT. All HBV genotypes displayed similar RT activity, except for genotype B, which demonstrated increased elongation activity.
Topics: Fluorescence; Hepatitis B virus; Humans; RNA-Directed DNA Polymerase
PubMed: 32171777
DOI: 10.1016/j.ab.2020.113642 -
Life (Basel, Switzerland) Mar 2021Nucles(t)ide analogs (NAs) are effective for chronic hepatitis B (CHB). NAs suppress hepatic decompensation and hepatocarcinogenesis, leading to a dramatic improvement...
Nucles(t)ide analogs (NAs) are effective for chronic hepatitis B (CHB). NAs suppress hepatic decompensation and hepatocarcinogenesis, leading to a dramatic improvement of the natural course of patients with CHB. However, renal dysfunction is becoming an important issue for the management of CHB. Renal dysfunction develops in patients with the long-term treatment of NAs including adefovir dipivoxil and tenofovir disoproxil fumarate. Recently, several studies have reported that the newly approved tenofovir alafenamide (TAF) has a safe profile for the kidney due to greater plasma stability. In this mini-review, we discuss the effectiveness of switching to TAF for NAs-related renal tubular dysfunction in patients with CHB.
PubMed: 33806752
DOI: 10.3390/life11030263 -
Clinical and Molecular Hepatology Jul 2020
Topics: Adenine; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Organophosphonates; Telbivudine; Tenofovir
PubMed: 32646206
DOI: 10.3350/cmh.2020.0099 -
Hepatology International Feb 2023It is a challenging issue regarding the optimal antiviral treatment of children with chronic hepatitis B (CHB). The efficacy comparison of interferon (IFN) or... (Meta-Analysis)
Meta-Analysis
BACKGROUND
It is a challenging issue regarding the optimal antiviral treatment of children with chronic hepatitis B (CHB). The efficacy comparison of interferon (IFN) or nucleos(t)ide analogs (NAs) monotherapy with their combination could better understand this issue.
METHODS
PubMed, EMBASE, Cochrane Library, Wanfang, CNKI, and abstracts of major international hepatology meetings were searched from inception to Feb 8, 2022. Randomized control trials and observational studies reporting the efficacy of combination therapy with IFN and NAs in children with CHB were eligible.
RESULTS
A total of 17 studies were included. Compared with IFN monotherapy, combination therapy with IFN and NAs was significantly associated with increased rates of HBV DNA undetectable, HBeAg clearance, HBeAg seroconversion, alanine transaminase (ALT) normalization as well as the composite treatment response both at the end of treatment and during the follow-up period (RRs ranged from 1.23 to 1.75). A favorable trend for HBsAg seroconversion was found in IFN plus NAs-treated children, but not for the HBsAg clearance at the end of treatment. Although a similar trend towards the superiority of the combination therapy versus NAs monotherapy was observed (RRs ranged from 1.24 to 2.33) except for the HBV DNA undetectable rate at the end of treatment, the number of reported studies was limited.
CONCLUSIONS
Combination therapy with IFN and NAs is more effective than IFN monotherapy in viral suppression and serological response for children with CHB. More studies were still needed to reveal the efficacy of this combination therapy compared with NAs monotherapy.
Topics: Humans; Child; Interferons; Nucleosides; Hepatitis B, Chronic; Hepatitis B Surface Antigens; Hepatitis B e Antigens; DNA, Viral; Treatment Outcome; Antiviral Agents; Drug Therapy, Combination
PubMed: 36469299
DOI: 10.1007/s12072-022-10415-7 -
Antiviral Research Apr 2020We designed, synthesized and identified a novel nucleoside derivative, 4'-C-cyano-7-deaza-7-fluoro-2'-deoxyadenosine (CdFA), which exerts potent anti-HBV activity (IC...
We designed, synthesized and identified a novel nucleoside derivative, 4'-C-cyano-7-deaza-7-fluoro-2'-deoxyadenosine (CdFA), which exerts potent anti-HBV activity (IC ~26 nM) with favorable hepatocytotoxicity (CC ~56 μM). Southern blot analysis using wild-type HBV (HBV)-encoding-plasmid-transfected HepG2 cells revealed that CdFA efficiently suppresses the production of HBV (IC = 153.7 nM), entecavir (ETV)-resistant HBV carrying L180M/S202G/M204V substitutions (HBV; IC = 373.2 nM), and adefovir dipivoxil (ADV)-resistant HBV carrying A181T/N236T substitutions (HBV; IC192.6 nM), whereas ETV and ADV were less potent against HBV and HBV (IC: >1,000 and 4,022.5 nM, respectively). Once-daily peroral administration of CdFA to human-liver-chimeric mice over 14 days (1 mg/kg/day) comparably blocked HBV and HBV viremia by 0.7 and 1.2 logs, respectively, without significant changes in body-weight or serum human-albumin levels, although ETV only slightly suppressed HBV viremia (CdFA vs ETV; p = 0.032). Molecular modeling suggested that ETV-TP has good nonpolar interactions with HBV reverse transcriptase (RT)'s Met204 and Asp205, while CdFA-TP fails to interact with Met204, in line with the relatively inferior activity against HBV of CdFA compared to ETV (IC: 0.026 versus 0.003 nM). In contrast, the 4'-cyano of CdFA-TP forms good nonpolar contacts with RT's Leu180 and RT's Met180, while ETV-TP loses interactions with RT's Met180, explaining in part why ETV is less potent against HBV than CdFA. The present results show that CdFA exerts potent activity against HBV, HBV and HBV with enhanced safety and that 7-deaza-7-fluoro modification confers potent activity against drug-resistant HBV variants and favorable safety, shedding light to further design more potent and safer anti-HBV nucleoside analogs.
Topics: Adenine; Animals; Antiviral Agents; Drug Resistance, Viral; Guanine; Hep G2 Cells; Hepatitis B virus; Hepatitis B, Chronic; Humans; Mice; Mice, Transgenic; Models, Molecular; Nucleosides; Organophosphonates; Viral Load
PubMed: 32084506
DOI: 10.1016/j.antiviral.2020.104744 -
American Journal of Physiology. Heart... Jan 2021edema toxin (ET) inhibited lethal toxin-stimulated pulmonary artery pressure (Ppa) and increased lung cAMP levels in our previous study. We therefore examined whether...
edema toxin (ET) inhibited lethal toxin-stimulated pulmonary artery pressure (Ppa) and increased lung cAMP levels in our previous study. We therefore examined whether ET inhibits hypoxic pulmonary vasoconstriction (HPV). Following baseline hypoxic measures in isolated perfused lungs from healthy rats, compared with diluent, ET perfusion reduced maximal Ppa increases (mean ± SE percentage of maximal Ppa increase with baseline hypoxia) during 6-min hypoxic periods (FIO = 0%) at 120 min (16 ± 6% vs. 51 ± 6%, = 0.004) and 180 min (11.4% vs. 55 ± 6%, = 0.01). Protective antigen-mAb (PA-mAb) and adefovir inhibit host cell edema factor uptake and cAMP production, respectively. In lungs perfused with ET following baseline measures, compared with placebo, PA-mAb treatment increased Ppa during hypoxia at 120 and 180 min (56 ± 6% vs. 10 ± 4% and 72 ± 12% vs. 12 ± 3%, respectively, ≤ 0.01) as did adefovir (84 ± 10% vs. 16.8% and 123 ± 21% vs. 26 ± 11%, respectively, ≤ 0.01). Compared with diluent, lung perfusion with ET for 180 min reduced the slope of the relationships between Ppa and increasing concentrations of endothelin-1 (ET-1) (21.12 ± 2.96 vs. 3.00 ± 0.76 × 10 cmHO/M, < 0.0001) and U46619, a thromboxane A2 analogue (7.15 ± 1.01 vs. 3.74 ± 0.31 × 10 cmHO/M, = 0.05) added to perfusate. In lungs isolated from rats after 15 h of in vivo infusions with either diluent, ET alone, or ET with PA-mAb, compared with diluent, the maximal Ppa during hypoxia and the slope of the relationship between change in Ppa and ET-1 concentration added to the perfusate were reduced in lungs from animals challenged with ET alone ( ≤ 0.004) but not with ET and PA-mAb together ( ≥ 0.73). Inhibition of HPV by ET could aggravate hypoxia during anthrax pulmonary infection. The most important findings here are edema toxin's potent adenyl cyclase activity can interfere with hypoxic pulmonary vasoconstriction, an action that could worsen hypoxemia during invasive anthrax infection with lung involvement. These findings, coupled with other studies showing that lethal toxin can disrupt pulmonary vascular integrity, indicate that both toxins can contribute to pulmonary pathophysiology during infection. In combination, these investigations provide a further basis for the use of antitoxin therapies in patients with worsening invasive anthrax disease.
Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Antibodies, Monoclonal; Antigens, Bacterial; Arterial Pressure; Bacterial Toxins; Cyclic AMP; Disease Models, Animal; Hypoxia; Lung; Male; Pulmonary Artery; Rats, Sprague-Dawley; Second Messenger Systems; Up-Regulation; Vasoconstriction; Vasoconstrictor Agents; Rats
PubMed: 33064559
DOI: 10.1152/ajpheart.00362.2020 -
Biomedicines Jan 2022Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B...
Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient's serum were cloned into the replication-competent HBV 1.2 mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.
PubMed: 35203489
DOI: 10.3390/biomedicines10020282 -
Clinical Drug Investigation Sep 2019Oral nucleoside/nucleotide analogues (NAs) have been advocated for chronic hepatitis B (CHB) treatment with good efficacy. However, less attention has been put on their... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVE
Oral nucleoside/nucleotide analogues (NAs) have been advocated for chronic hepatitis B (CHB) treatment with good efficacy. However, less attention has been put on their adverse events. Therefore, a Bayesian network meta-analysis (NMA) was performed to evaluate the relative safety of five NAs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate) in CHB treatment among adults.
METHODS
Eligible randomized clinical trials (RCTs) and prospective cohort studies were systematically and thoroughly searched until May 1, 2019. Poisson-prior-based Bayesian NMA was performed to synthesize both direct and indirect evidence with reporting hazard ratios (HRs) and 95% credible intervals (CrIs) for serious adverse events (SAEs) and hepatic/renal impairments.
RESULTS
Thirty-three RCTs and 11 prospective cohort studies were identified. As to SAEs, no statistically significant difference was found of any comparison among five NAs. In terms of hepatotoxicity, lamivudine was safer than telbivudine (HR 0.45; 95% CrI 0.21, 0.85), and entecavir increased the risk by 102% (entecavir vs lamivudine: HR 2.02; 95% CrI 1.19, 3.27).
CONCLUSIONS
The findings from this large NMA could influence clinical practice, and the methodological framework of this study could provide evidence-based support to analyze sparse safety data in the field.
Topics: Adenine; Antiviral Agents; Bayes Theorem; Guanine; Hepatitis B, Chronic; Humans; Lamivudine; Network Meta-Analysis; Organophosphonates; Prospective Studies; Telbivudine; Tenofovir
PubMed: 31228017
DOI: 10.1007/s40261-019-00802-8