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Infectious Agents and Cancer 2019Hepatitis B caused by HBV is a serious public health hazard prevalent worldwide including Bangladesh. Few scattered molecular studies of HBV have been reported in... (Review)
Review
BACKGROUND AND AIM
Hepatitis B caused by HBV is a serious public health hazard prevalent worldwide including Bangladesh. Few scattered molecular studies of HBV have been reported in Bangladesh. This study aimed to analyze the genetic variability of RT/HBsAg overlapping region of HBV isolates of Bangladesh and determination of correlation among the genotype/serotype and HBsAg escape and/or drug-resistant mutations.
METHODS
A total of 97 complete HBsAg sequences of Bangladeshi HBV isolates from 2005 to 2017 from NCBI GenBank were extracted and analyzed using several HBV bioinformatics tools such as Geno2pheno-HBV, HBV Serotyper, HIV-Grade:HBV-Tool, and CLC sequence viewer.
RESULTS
The prevalence of genotypes A, C, and D are 18, 46 and 35% which correspond to serotype , , and respectively. The prevalence of HBsAg escape mutations is 51% and most of which (62%) are found in the genotype D followed by 32% in genotype C and 6% in genotype A. Interestingly most (24/36) of the sequences of HBsAg escape mutations contained 128 V mutant which all belongs to only serotype (Genotype D). Prevalence of drug-resistant mutations is ~ 11%, most of which are from genotype C (63.64%) and D (36.36%). Lamivudine resistant mutations were found in ~ 11% of sequences followed by Telbivudine 10% and Adefovir 3% where Tenofovir showed susceptibility to all 97 sequences. Moreover, 7 among of 97 sequences showed both HBsAg and drugs resistant mutations and none of them are found due to the same nucleotide substitutions.
CONCLUSION
There is a strong correlation among the genotype/serotype and HBsAg escape and/or drug-resistant mutations. This meta-analytical review will be helpful for genotype-serotype prediction by PCR-based diagnosis and development of vaccine and/or diagnostic kits, and the treatment against HBV infection in the future.
PubMed: 31709005
DOI: 10.1186/s13027-019-0253-6 -
Molecules (Basel, Switzerland) Feb 2021Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV),... (Review)
Review
Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogues, namely tenofovir disoproxil fumarate (Viread) and tenofovir alafenamide (Vemlidy) against HIV and HBV infections and adefovir dipivoxil (Hepsera) against HBV infections; (ii) two thymidine nucleoside analogues, namely brivudine (Zostex) against HSV-1 and VZV infections and stavudine (Zerit) against HIV infections; (iii) two guanosine analogues, namely valacyclovir (Valtrex, Zelitrex) against HSV and VZV and rabacfosadine (Tanovea-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analogue, namely cidofovir (Vistide) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clinical use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogues supports their development to treat or prevent current and emerging infectious diseases worldwide.
Topics: Anniversaries and Special Events; Antiviral Agents; Drug Discovery; History, 20th Century; History, 21st Century; Humans; Nucleosides; Nucleotides; Virus Diseases; Viruses
PubMed: 33572409
DOI: 10.3390/molecules26040923 -
Gastroenterology Clinics of North... Jun 2020Half a century after its discovery, hepatitis delta remains a pertinent global health issue with a major clinical impact in endemic regions and an underestimated... (Review)
Review
Half a century after its discovery, hepatitis delta remains a pertinent global health issue with a major clinical impact in endemic regions and an underestimated prevalence worldwide. Hepatitis delta virus infection follows a challenging clinical course and is responsible for significant liver-related morbidity. Although the only currently available treatment (pegylated interferon) does not provide consistent results, emerging therapeutic options are promising. This article explores the epidemiology, natural history, as well as current and potential therapeutic options for hepatitis delta virus infection.
Topics: Adenine; Antibodies, Viral; Antiviral Agents; Biomarkers; Carcinoma, Hepatocellular; Global Health; Hepatitis D; Hepatitis Delta Virus; Hepatitis delta Antigens; Humans; Interferon alpha-2; Lamivudine; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Organophosphonates; Prevalence; RNA, Viral; Risk; Serologic Tests
PubMed: 32389361
DOI: 10.1016/j.gtc.2020.01.004 -
Hepatology Communications Jan 2024Recent clinical studies have suggested that the risk of developing HCC might be lower in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate than...
BACKGROUND
Recent clinical studies have suggested that the risk of developing HCC might be lower in patients with chronic hepatitis B receiving tenofovir disoproxil fumarate than in patients receiving entecavir, although there is no difference in biochemical and virological remission between the 2 drugs.
METHODS
The effects of nucleoside analogs (NsAs; lamivudine and entecavir) or nucleotide analogs (NtAs; adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide) on cell growth and the expression of growth signaling molecules in hepatoma cell lines and PXB cells were investigated in vitro. The tumor inhibitory effects of NsAs or NtAs were evaluated using a mouse xenograft model, and protein phosphorylation profiles were investigated. The binding of NsAs or NtAs to the insulin receptor (INSR) was investigated by thermal shift assays.
RESULTS
NtAs, but not NsAs, showed direct growth inhibitory effects on hepatoma cell lines in vitro and a mouse model in vivo. A phosphoprotein array revealed that INSR signaling was impaired and the levels of phosphorylated (p)-INSRβ and downstream molecules phosphorylated (p)-IRS1, p-AKT, p-Gab1, and p-SHP2 were substantially reduced by NtAs. In addition, p-epidermal growth factor receptor and p-AKT levels were substantially reduced by NtAs. Similar findings were also found in PXB cells and nontumor lesions of liver tissues from patients with chronic hepatitis B. Prodrug NtAs, but not their metabolites (adefovir, adefovir monophosphate, adefovir diphosphate, tenofovir, tenofovir monophosphate, and tenofovir diphosphate), had such effects. A thermal shift assay showed the binding of NtAs to INSRβ.
CONCLUSIONS
NtAs (adefovir disoproxil, tenofovir disoproxil fumarate, and tenofovir alafenamide), which are adenine derivative acyclic nucleotide analogs, potentially bind to the ATP-binding site of growth factor receptors and inhibit their autophosphorylation, which might reduce the risk of HCC in patients with chronic hepatitis B.
Topics: Humans; Hepatitis B virus; Carcinoma, Hepatocellular; Hepatitis B, Chronic; Proto-Oncogene Proteins c-akt; Liver Neoplasms; Hepatitis B; Hepatocytes; Tenofovir; Intercellular Signaling Peptides and Proteins; Nucleotides
PubMed: 38180972
DOI: 10.1097/HC9.0000000000000351 -
Journal of Hepatology May 2021While certain nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are efficacious in treating HBV infection, their effects are yet to be optimized and the emergence...
BACKGROUND & AIMS
While certain nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are efficacious in treating HBV infection, their effects are yet to be optimized and the emergence of NRTI-resistant HBV variants is an issue because of the requirement for lifelong treatment. The development of agents that more profoundly suppress wild-type and drug-resistant HBVs, and that have a long-acting effect, are crucial to improve patient outcomes.
METHODS
Herein, we synthesized a novel long-acting 4'-modified NRTI termed E-CFCP. We tested its anti-HBV activity in vitro, before evaluating its anti-HBV activity in HBV-infected human-liver-chimeric mice (PXB-mice). E-CFCP's long-acting features and E-CFCP-triphosphate's interactions with the HBV reverse transcriptase (HBV-RT) were examined.
RESULTS
E-CFCP potently blocked HBV production (IC1.8 nM) in HepG2.2.15 cells and HBV (IC=0.7 nM), entecavir (ETV)-resistant HBV (IC=77.5 nM), and adefovir-resistant HBV production (IC=14.1 nM) in Huh7 cells. E-CFCP profoundly inhibited intracellular HBV DNA production to below the detection limit, but ETV and tenofovir alafenamide (TAF) failed to do so. E-CFCP also showed less toxicity than ETV and TAF. E-CFCP better penetrated hepatocytes and was better tri-phosphorylated; E-CFCP-triphosphate persisted intracellularly for longer than ETV-triphosphate. Once-daily peroral E-CFCP administration over 2 weeks (0.02~0.2 mg/kg/day) reduced HBV-viremia by 2-3 logs in PXB-mice without significant toxicities and the reduction persisted over 1-3 weeks following treatment cessation, suggesting once-weekly dosing capabilities. E-CFCP also reduced HBV-viremia by 2 logs over 2 weeks, while ETV completely failed to reduce HBV-viremia. E-CFCP's 4'-cyano and fluorine interact with both HBV-RT and HBV -RT via Van der Waals and polar forces, being important for E-CFCP-triphosphate's interactions and anti-HBV potency.
CONCLUSION
E-CFCP represents the first reported potential long-acting NRTI with potent activity against wild-type and treatment-resistant HBV.
LAY SUMMARY
Although there are currently effective treatment options for HBV, treatment-resistant variants and the need for lifelong therapy pose a significant challenge. Therefore, the development of new treatment options is crucial to improve outcomes and quality of life. Herein, we report preclinical evidence showing that the anti-HBV agent, E-CFCP, has potent activity against wild-type and treatment-resistant variants. In addition, once-weekly oral dosing may be possible, which is preferrable to the current daily dosing regimens.
Topics: Animals; Delayed-Action Preparations; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Drug Development; Drug Resistance, Viral; Hepatitis B; Hepatitis B virus; Humans; Mice; RNA-Directed DNA Polymerase; Reverse Transcriptase Inhibitors; Time
PubMed: 33333207
DOI: 10.1016/j.jhep.2020.12.006 -
Annals of Translational Medicine Sep 2022Chronic hepatitis B (CHB) affects a vast population globally. A variety of drugs are available for the treatment of CHB, including tenofovir (TDF) and adefovir (ADV)....
Comparing the efficacy and safety of tenofovir and adefovir or combined drug treatment for the treatment of chronic hepatitis B infection: a systematic review and meta-analysis.
BACKGROUND
Chronic hepatitis B (CHB) affects a vast population globally. A variety of drugs are available for the treatment of CHB, including tenofovir (TDF) and adefovir (ADV). However, the efficacy of monotherapy drug treatment is inconclusive, the safety and efficacy of TDF remain unclear, more data are needed to be included and combined drug treatment is considered to exhibit higher efficacy. To explore this issue, we performed a current literature review and meta-analysis to compare the efficacy and safety of ADV TDF, TDF ADV + lamivudine (LAM); TDF ADV + entecavir (ETV).
METHODS
We systematically searched China National Knowledge Infrastructure, the Cochrane Library, Embase, PubMed, Chinese VIP, and Wanfang Data, for relevant clinical trials since July 2015, all included studies were based on PICOS principles and evaluated independently by the reviewers in accordance with the Cochrane Handbook (Rob2.0). A meta-analysis was performed by using Review Manager 5.4.
RESULTS
We included a total of 32 studies, including 31 randomized controlled trials and one retrospective study involving 2,473 patients. The results revealed a low risk of bias in included studies, that the virologic response of TDF was superior to ADV (P<0.05). And TDF was also superior to ADV in Serum creatinine levels, Immunologic function, and safety profile. However, when ADV was combined with other medications, it was superior to TDF in alanine aminotransferase (ALT) level and Tbil level and adverse reactions, but on other indicators, TDF was superior to drug combination therapy.
CONCLUSIONS
Results showed that TDF was superior to ADV in the parameters of ALT, hepatitis B virus (HBV)-DNA reduction, HBeAg-negative conversion rate, safety, and total bilirubin levels in patients with CHB. However, when ADV was combined with LAM or ETV, they often showed the same therapeutic effect as TDF in parameters such as ALT level and Tbil level and combined therapy can effectively reduce the occurrence of adverse reactions. In this study, because the sample source countries were limited, a greater number of global studies are needed in the future to verify the current findings.
PubMed: 36267714
DOI: 10.21037/atm-22-3747 -
BMC Infectious Diseases Sep 2021Entecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and...
BACKGROUND
Entecavir (ETV) is recommended as a first-line anti-HBV treatment. However, many chronic hepatitis B patients initiate anti-HBV treatment such as lamivudine and telbivudine with low genetic barriers in China, which leads to compensatory mutations and increases the rate of ETV resistance. The management of ETV resistance in China is an essential clinical issue.
METHODS
Patients from 2011 to 2017 with nucleos(t)ide analog resistance were screened and 72 patients with ETV resistance were included. These patients received different rescue therapies including an ETV and adefovir (ADV) combination therapy group (n = 25), a tenofovir (TDF) monotherapy group (n = 27), and an ETV and TDF combination therapy group (n = 20). Virologic, biochemical, and serologic responses were compared among the three groups.
RESULTS
The rate of ETV resistance among all HBV-resistant variants increased from 6.04% in 2011 to 15.02% in 2017. TDF monotherapy and TDF combination groups showed similar rates of negative HBV DNA at 48 weeks (74.07% vs 70.00%, P > 0.05), while the ETV and ADV group showed the worst virologic response (28.00%). Also, TDF monotherapy and TDF combination therapy showed similar decline of HBV DNA at weeks 12, 24, and 48. There was no significant difference in the rates of HBeAg clearance, ALT normalization, and abnormal renal function among the three groups.
CONCLUSIONS
TDF monotherapy showed a comparable virologic response to TDF and ETV combination therapy and a better virologic response than ETV and ADV combination therapy. Thus, TDF monotherapy is the preferred rescue therapy for ETV resistance.
Topics: Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Drug Therapy, Combination; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Treatment Outcome; Viral Load
PubMed: 34488678
DOI: 10.1186/s12879-021-06554-1 -
Clinical Gastroenterology and... Feb 2022It remains unknown whether tenofovir alafenamide (TAF) could replace tenofovir disoproxil fumarate (TDF) in patients with drug-resistant hepatitis B virus (HBV). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
It remains unknown whether tenofovir alafenamide (TAF) could replace tenofovir disoproxil fumarate (TDF) in patients with drug-resistant hepatitis B virus (HBV).
METHODS
In this multicenter randomized non-inferiority trial, 174 patients with HBV resistant to multiple drugs (lamivudine, entecavir, and/or adefovir) under TDF monotherapy for ≥96 weeks were randomized 1:1 to switch to TAF (n = 87) or continue TDF (n = 87) for 48 weeks. The primary endpoint was proportion of patients with HBV DNA <60 IU/mL at week 48.
RESULTS
At baseline, 84 and 80 patients had HBV DNA <60 IU/mL in the TAF and TDF groups, respectively. At week 48, the proportion of patients with HBV DNA <60 IU/mL was 98.9% (86/87) in TAF group, showing non-inferiority to TDF group (97.7%, 85/87; difference, 1.1%; 95% confidence interval, -2.7% to 5.0%). Changes in median alanine aminotransferase at week 48 from baseline were statistically different between TAF and TDF groups (-3 IU/L vs +2 IU/L; P = .02). TAF group showed a statistically greater increase in bone mineral density at spine (+1.84% vs +0.08%; P = .01) and numerically higher increase in mean estimated glomerular filtration rate (+8.2% vs +4.5%; P = .06) compared with TDF group. Compared with TDF group, TAF group showed significantly greater increases in mean body weight (0.71 vs -0.37 kg; P = .01) and total, low-density lipoprotein, and high-density lipoprotein cholesterol levels (P < .001 for all) at week 48 from baseline.
CONCLUSIONS
TAF could be substituted for TDF in patients with multidrug-resistant HBV for improved bone and renal safety without a loss of efficacy. However, increases in body weight and cholesterol levels with TAF treatment would be a concern. ClinicalTrials.gov no.: NCT03241641.
Topics: Alanine; Antiviral Agents; Hepatitis B; Hepatitis B, Chronic; Humans; Tenofovir; Treatment Outcome
PubMed: 33962041
DOI: 10.1016/j.cgh.2021.04.045 -
Journal of Chromatography. B,... Sep 2019As a tool to be used in transporter-mediated drug-drug interaction studies, a sensitive LC-MS/MS method for the simultaneous quantification of adefovir and pitavastatin...
As a tool to be used in transporter-mediated drug-drug interaction studies, a sensitive LC-MS/MS method for the simultaneous quantification of adefovir and pitavastatin in human plasma and adefovir in urine was developed and successfully validated. Plasma samples were processed by protein precipitation using methanol with a subsequent concentrating step. Urine samples were diluted using 0.1% formic acid. Separation was achieved on a Synergy Polar-RP reversed phase column (50 × 4.6 mm, 2.5 μm) in gradient elution using a mobile phase composed of water and 0.1% formic acid and a mixture of methanol and acetonitrile (50:50, v/v) containing 0.1% formic acid at a flow rate of 1.0 mL/min. The linear range covered concentrations from 0.273 to 52.6 ng/mL for adefovir and from 0.539 to 104.2 ng/mL for pitavastatin in human plasma, respectively. The calibration curve for adefovir in urine ranged from 0.104 to 10.0 μg/mL. The weighted linear regression (1/conc) implied excellent linearity with correlation coefficients ≥0.999.
Topics: Adenine; Chromatography, High Pressure Liquid; Humans; Organophosphonates; Plasma; Quinolines; Tandem Mass Spectrometry
PubMed: 31330406
DOI: 10.1016/j.jchromb.2019.121718 -
Bioorganic & Medicinal Chemistry Aug 2019The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and...
Synthesis, pharmacological evaluation, and mechanistic study of adefovir mixed phosphonate derivatives bearing cholic acid and l-amino acid moieties for the treatment of HBV.
The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono l-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 6c as the optimal molecular candidate, with the highest antiviral activity (EC 0.42 μmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 6c exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 6c cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 6c indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and l-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 6c is a potential candidate as an anti-HBV therapy and therefore merits further investigation.
Topics: Adenine; Antiviral Agents; Cholic Acid; Hepatitis B virus; Humans; Organophosphonates
PubMed: 31301948
DOI: 10.1016/j.bmc.2019.07.012