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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 -
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 -
Mayo Clinic Proceedings Oct 2011Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The... (Review)
Review
Most viral diseases, with the exception of those caused by human immunodeficiency virus, are self-limited illnesses that do not require specific antiviral therapy. The currently available antiviral drugs target 3 main groups of viruses: herpes, hepatitis, and influenza viruses. With the exception of the antisense molecule fomivirsen, all antiherpes drugs inhibit viral replication by serving as competitive substrates for viral DNA polymerase. Drugs for the treatment of influenza inhibit the ion channel M(2) protein or the enzyme neuraminidase. Combination therapy with Interferon-α and ribavirin remains the backbone treatment for chronic hepatitis C; the addition of serine protease inhibitors improves the treatment outcome of patients infected with hepatitis C virus genotype 1. Chronic hepatitis B can be treated with interferon or a combination of nucleos(t)ide analogues. Notably, almost all the nucleos(t) ide analogues for the treatment of chronic hepatitis B possess anti-human immunodeficiency virus properties, and they inhibit replication of hepatitis B virus by serving as competitive substrates for its DNA polymerase. Some antiviral drugs possess multiple potential clinical applications, such as ribavirin for the treatment of chronic hepatitis C and respiratory syncytial virus and cidofovir for the treatment of cytomegalovirus and other DNA viruses. Drug resistance is an emerging threat to the clinical utility of antiviral drugs. The major mechanisms for drug resistance are mutations in the viral DNA polymerase gene or in genes that encode for the viral kinases required for the activation of certain drugs such as acyclovir and ganciclovir. Widespread antiviral resistance has limited the clinical utility of M(2) inhibitors for the prevention and treatment of influenza infections. This article provides an overview of clinically available antiviral drugs for the primary care physician, with a special focus on pharmacology, clinical uses, and adverse effects.
Topics: Acyclovir; Adenine; Amantadine; Antiviral Agents; Comorbidity; Drug Therapy, Combination; Foscarnet; Ganciclovir; Guanine; HIV Infections; Hepatitis; Hepatitis B, Chronic; Hepatitis C; Herpesviridae Infections; Humans; Influenza, Human; Interferons; Lamivudine; Nucleosides; Oligopeptides; Organophosphonates; Oseltamivir; Proline; Protease Inhibitors; Pyrimidinones; Ribavirin; Telbivudine; Thymidine; Valacyclovir; Valganciclovir; Valine; Virus Replication; Zanamivir
PubMed: 21964179
DOI: 10.4065/mcp.2011.0309 -
The Journal of International Medical... Oct 2020More than 150 cases of Fanconi syndrome (FS) or hypophosphatemia osteomalacia induced by low-dose adefovir dipivoxil (ADV) have been reported since 2002, when ADV was... (Review)
Review
More than 150 cases of Fanconi syndrome (FS) or hypophosphatemia osteomalacia induced by low-dose adefovir dipivoxil (ADV) have been reported since 2002, when ADV was introduced for the long-term treatment of hepatitis B virus (HBV) infection. Because the life expectancy of HBV-infected individuals has increased, the adverse effects of long-term treatment with antiviral therapies are increasingly observed, and nephrotoxicity is one of the most severe adverse effects of ADV. Therefore, the number of cases may be far higher than reported. Moreover, ADV-induced FS is often misdiagnosed or diagnosed long after it first develops. ADV-induced FS may seriously decrease patient quality of life and lead to bone fractures and even disability. Although progress has been made in the identification of biomarkers and treatments, few systematic clinical guidelines or clinical reviews for FS induced by ADV have been reported. In this study, we highlighted the recent progress toward understanding of FS induced by ADV, described a clinical case, and summarized the primary characteristics and laboratory findings of this disease.
Topics: Adenine; Antiviral Agents; Fanconi Syndrome; Hepatitis B virus; Hepatitis B, Chronic; Humans; Organophosphonates; Quality of Life
PubMed: 33100076
DOI: 10.1177/0300060520954713 -
Experimental Hematology & Oncology Nov 2022Acute promyelocytic leukemia (APL) is highly aggressive and is frequently associated with disseminated intravascular coagulation and high early death rates. Although...
Acute promyelocytic leukemia (APL) is highly aggressive and is frequently associated with disseminated intravascular coagulation and high early death rates. Although all-trans retinoic acid (RA) induces complete remission in a high proportion of patients with APL, there are limited treatments for APL patients with RA resistance. Here we report an atypical APL patient, with an APL-like disease that developed very slowly without anti-leukemia therapy for nearly 2 years. During that time, the patient only intermittently received anti-HBV drugs, i.e., the combination of adefovir dipivoxil (ADV) and entecavir (ETV), leading us to hypothesize that ADV and/or ETV could inhibit APL progression. Our results showed that anti-HBV drugs ADV and ETV both exhibited significantly inhibitory effects on APL cells, and ADV indicated a much greater cytotoxic effect than ETV on APL cells. We further found that ADV significantly promoted APL cell differentiation and apoptosis, thereby restraining the progression of APL. Most importantly, our study uncovered a novel mechanism of ADV prohibiting APL progression, which was mediated, at least in part, by inhibition of TRIB3 and degradation of the oncoprotein PML-RARA, therefore leading to APL cell differentiation and apoptosis. Taken together, our study demonstrated that ADV, an anti-HBV drug, had significantly inhibitory effects on APL, and provided a novel therapeutic strategy for APL patients with RA resistance.
PubMed: 36404334
DOI: 10.1186/s40164-022-00355-1 -
World Journal of Gastroenterology Dec 2012Nucleos(t)ide analogues (NA) are a breakthrough in the treatment and management of chronic hepatitis B. NA could suppress the replication of hepatitis B virus (HBV) and... (Review)
Review
Nucleos(t)ide analogues (NA) are a breakthrough in the treatment and management of chronic hepatitis B. NA could suppress the replication of hepatitis B virus (HBV) and control the progression of the disease. However, drug resistance caused by their long-term use becomes a practical problem, which influences the long-term outcomes in patients. Liver transplantation is the only choice for patients with HBV-related end-stage liver disease. But, the recurrence of HBV after transplantation often caused by the development of drug resistance leads to unfavorable outcomes for the recipients. Recently, the multi-drug resistance (MDR) has become a common issue raised due to the development and clinical application of a variety of NA. This may complicate the antiviral therapy and bring poorly prognostic outcomes. Although clinical evidence has suggested that combination therapy with different NA could effectively reduce the viral load in patients with MDR, the advent of new antiviral agents with high potency and high genetic barrier to resistance brings hope to antiviral therapy. The future of HBV researches relies on how to prevent the MDR occurrence and develop reasonable and effective treatment strategies. This review focuses on the diagnostic and therapeutic progress in MDR caused by the anti-HBV NA and describes some new research progress in this field.
Topics: Adenine; Antiviral Agents; Drug Resistance, Multiple; Guanine; Hepatitis B e Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Interferons; Lamivudine; Liver Transplantation; Mutation; Nucleosides; Nucleotides; Organophosphonates; Prognosis; Tenofovir; Viral Load
PubMed: 23326119
DOI: 10.3748/wjg.v18.i48.7149 -
International Journal of Infectious... Mar 2010Long-term lamivudine (LAM) and adefovir (ADV) treatment has been found to induce the emergence of drug-resistant hepatitis B virus (HBV) in a significant number of...
OBJECTIVE
Long-term lamivudine (LAM) and adefovir (ADV) treatment has been found to induce the emergence of drug-resistant hepatitis B virus (HBV) in a significant number of patients with chronic hepatitis B (CHB) infection. The aim of our study was to evaluate the LAM and ADV mutations detected in our patient group.
MATERIALS AND METHODS
Twenty-four patients diagnosed with CHB were enrolled in this study. The patient group consisted of those who had received 6 months of treatment with interferon-alpha and who did not response to this therapy. Patients were evaluated based on virologic and serologic response to therapy, and were classified as responders or non-responders. The treatment of non-responders continued with LAM (3mg/kg/d, maximum 100mg/d). Due to a lack of response to treatment, ADV (10mg/g) was added to the treatment regimen of eight young adult patients. The mutations associated with HBV drug resistance were investigated using reverse hybridization methods and PCR.
RESULTS
The mutation studies indicated that 14 (58.4%) of the patients had resistance. Three patients developed ADV-associated mutations (A181T), one after 18 months of ADV; the other two had undergone 18 and 36 months of LAM therapy without ADV exposure. Although the average LAM treatment period of the patients with LAM resistance was longer than for those in whom no resistance was detected, no statistically significant difference was found.
CONCLUSIONS
HBV treatment with nucleoside analogues results in the development of mutant strains, leading to drug resistance. Therefore genotypic resistance testing is important in planning and monitoring HBV treatment.
Topics: Adenine; Adolescent; Antiviral Agents; Child; Drug Administration Schedule; Drug Resistance, Viral; Female; Genotype; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Mutation; Organophosphonates; Reverse Transcriptase Inhibitors; Time Factors; Young Adult
PubMed: 19665408
DOI: 10.1016/j.ijid.2009.04.002 -
Oncotarget May 2016Currently, no consensus exists regarding the optimal oral prophylactic regimens for hepatitis B surface antigen seropositive patients undergoing chemotherapy. We aimed... (Comparative Study)
Comparative Study Meta-Analysis Review
Systematic review with network meta-analysis: Comparative efficacy of oral nucleos(t)ide analogues for the prevention of chemotherapy-induced hepatitis B virus reactivation.
OBJECTIVES
Currently, no consensus exists regarding the optimal oral prophylactic regimens for hepatitis B surface antigen seropositive patients undergoing chemotherapy. We aimed to compare the efficacy of oral nucleos(t)ide analogues (NAs), including lamivudine, entecavir, adefovir, telbivudine and tenofovir, for the prevention of chemotherapy-induced hepatitis B virus (HBV) reactivation and its related morbidity and mortality in patients with chronic HBV (CHB) infection.
RESULTS
Fifty-two eligible articles consisting of 3892 participants were included. For HBV reactivation, prophylactic treatment with NAs were all significantly superior to no prophylaxis, with odds ratio (OR) from 0.00 (95% confidence interval [CI] 0.00~0.04) for the most effective intervention (tenofovir) to 0.10 (95% CI 0.06~0.14) for the least effective intervention (lamivudine). For secondary outcomes, prophylaxis with NAs also significantly outperformed observation. The results suggested that entecavir reduced the risk of HBV related hepatitis (predicted probability, 83%), HBV related death (68%) and all causes of hepatitis (97%) most efficaciously. It ranked second in decreasing all causes of death (34%).
MATERIALS AND METHODS
PubMed, Embase and Cochrane Library database were searched for controlled trials up to March 31, 2015. Primary outcome was the incidence of HBV reactivation. Secondary outcomes included the incidence of HBV-related hepatitis and death, all causes of hepatitis and death. Network meta-analysis combined direct and indirect evidence to estimate ORs for the clinical outcomes. A mean ranking and the probability of optimal therapeutic regime was obtained for each treatment based on clinical outcomes.
CONCLUSIONS
Available evidence suggests that prophylatic therapy with tenofovir and entecavir may be the most potent interventions in prevention of HBV reactivation and HBV-related morbidity and mortality for CHB infection patients undergoing chemotherapy.
Topics: Adenine; Antineoplastic Agents; Antiviral Agents; Controlled Clinical Trials as Topic; Guanine; Hepatitis B; Hepatitis B virus; Host-Pathogen Interactions; Humans; Lamivudine; Organophosphonates; Telbivudine; Thymidine; Virus Activation
PubMed: 27121321
DOI: 10.18632/oncotarget.8907 -
Medicine Dec 2016To assess the relationship between adefovir dipivoxil and renal function after anti-hepatitis B virus therapy and elucidate the risk factors involved. (Meta-Analysis)
Meta-Analysis
BACKGROUND
To assess the relationship between adefovir dipivoxil and renal function after anti-hepatitis B virus therapy and elucidate the risk factors involved.
METHODS
Based on the requirements of the Cochrane systematic review methodology, 21 observational articles on adefovir dipivoxil-associated renal dysfunction were obtained by searching various databases, between January 1, 1995 and July 1, 2016. The Newcastle Ottawa Scale was used to evaluate risk bias. Parameters for 4276 chronic hepatitis B patients were analyzed by Review Manager and R software, and glomerular filtration rate, creatinine clearance, and serum creatinine values were extracted to evaluate renal function.
RESULTS
Renal dysfunction was more likely to occur in patients receiving the adefovir dipivoxil therapy (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.40-2.80) than the none-adefovir dipivoxil group. Subgroup analysis showed that renal function predictive value is higher for glomerular filtration rate (OR 2.42, 95% CI 1.34-3.14), compared with serum creatinine levels (OR 1.51, 95% CI 0.75-3.04). The rate of adefovir dipivoxil-associated renal dysfunction was 12% (95% CI 0.08-0.16). Older patients and patients with renal insufficiency, hypertension, and diabetes mellitus were more prone to developing adefovir dipivoxil-associated renal dysfunction; however, integrated raw data were insufficient for further detailed analysis.
CONCLUSION
Long-term adefovir dipivoxil therapy is connected to renal dysfunction in chronic hepatitis B, necessitating the monitoring of kidney function.
Topics: Adenine; Creatinine; Glomerular Filtration Rate; Hepatitis B, Chronic; Humans; Kidney; Kidney Diseases; Organophosphonates; Risk Factors
PubMed: 27977591
DOI: 10.1097/MD.0000000000005578 -
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