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Journal of Hepatology Feb 2006The incidence and risk factors for adefovir-resistant HBV have not been clearly defined. (Comparative Study)
Comparative Study
BACKGROUND
The incidence and risk factors for adefovir-resistant HBV have not been clearly defined.
AIMS
To characterize the virologic response to adefovir, to determine the rate of adefovir resistance and to explore factors associated with initial virologic response (IVR) and adefovir resistance.
METHODS
All hepatitis B patients who received adefovir for > or =6 months at our center were prospectively monitored for virologic response and adefovir resistance.
RESULTS
Forty three patients were included; mean treatment duration was 18 months (range 6-45). Thirty four (79%) patients had prior lamivudine. IVR was observed in 44% patients and associated with higher pretreatment ALT (P = 0.05) and the absence of HBeAg (P = 0.02). Six (14%) patients were found to have adefovir-resistant mutations. The cumulative probability of genotypic resistance to adefovir at month 24 was 22%. Patients with adefovir resistance were more likely to have been switched from lamivudine to adefovir monotherapy (P = 0.01), to be older (P = 0.04), and to be infected with HBV genotype D (P = 0.02).
CONCLUSIONS
Roughly 50% of patients failed to achieve IVR on adefovir. The cumulative probability of adefovir resistance at 2 years was 22%. Our data suggest that combination of lamivudine and adefovir may prevent emergence of adefovir resistance in patients with lamivudine-resistant HBV.
Topics: Adenine; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Follow-Up Studies; Genotype; Hepatitis B virus; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Mutation; Organophosphonates; Polymerase Chain Reaction; Retrospective Studies; Treatment Outcome
PubMed: 16338024
DOI: 10.1016/j.jhep.2005.10.018 -
Medicine Sep 2015To reduce hepatitis B virus reinfection after liver transplantation (LT), patients often receive antihepatitis B immunoglobulin (HBIG) alone or combined with antiviral... (Observational Study)
Observational Study
To reduce hepatitis B virus reinfection after liver transplantation (LT), patients often receive antihepatitis B immunoglobulin (HBIG) alone or combined with antiviral nucleoside/nucleotide analogs (NUCs); however, proximal renal tubular dysfunction (RTD) that was induced by NUCs in liver recipients was rarely reported. Here, we analyzed RTD and renal impairment (RI) following adefovir (ADV) and lamivudine (LAM) treatment in liver recipients. We retrospectively reviewed medical records of patients treated with HBIG alone (group 1, n = 42) or combined with ADV or LAM (group 2, n = 21) after LT. We compared RTD and RI incidence during the 12 months after LT. An RTD diagnosis required manifestation of at least 3 of the following features: hypophosphatemia, RI, hypouricemia, proteinuria, or glucosuria. No significant differences were observed regarding sex, age, donor type, model of end-stage liver score, and estimated glomerular filtration rate at pre-LT between the 2 groups. Hepatitis B virus recurrence within 12 months was 4.8% in both groups (P = 1.000); however, the RTD incidence was 0% in group 1 and 19.0% in group 2 (P = 0.010). RI occurrence did not differ between the groups. The only risk factor for RI was HBIG administration combined with both LAM and ADV (odds ratio 11.27, 95% confidence interval 1.13-112.07, P = 0.039, vs HBIG alone). RTD occurred more frequently in patients treated with HBIG combined with LAM or ADV compared with HBIG alone. Thus, LAM or ADV therapy can induce RTD after LT, and when administered, liver recipients should be monitored.
Topics: Adenine; Female; Hepatitis B; Humans; Incidence; Kidney Diseases; Lamivudine; Liver Transplantation; Male; Middle Aged; Organophosphonates; Postoperative Complications; Recurrence; Republic of Korea; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors
PubMed: 26402818
DOI: 10.1097/MD.0000000000001569 -
Human Pathology Jul 2001This report investigates the pathomechanism of acute renal failure caused by toxic acute tubular necrosis after treatment with the antiretroviral agent adefovir. A...
This report investigates the pathomechanism of acute renal failure caused by toxic acute tubular necrosis after treatment with the antiretroviral agent adefovir. A 38-year-old white homosexual man with human immunodeficiency virus infection and no history of opportunistic infections was maintained on highly active antiretroviral therapy (HAART), including hydroxyurea, stavudine, indinavir, ritonavir, and adefovir dipivoxil. Histologic examination of the renal biopsy showed severe acute tubular degenerative changes primarily affecting the proximal tubules. On ultrastructural examination, proximal tubular mitochondria were extremely enlarged and dysmorphic with loss and disorientation of their cristae. Functional histochemical stains for mitochondrial enzymes revealed focal tubular deficiency of cytochrome C oxidase (COX), a respiratory chain enzyme partially encoded by mitochondrial DNA (mtDNA), with preservation of succinate dehydrogenase, a respiratory chain enzyme entirely encoded by nuclear DNA (nDNA). Immunoreactivity for COX subunit I (encoded by mtDNA) was weak to undetectable in most tubular epithelial cells, although immunoreactivities for COX subunit IV and iron sulfur subunit of respiratory complex III (both encoded by nDNA) were well preserved in all renal tubular cells. Single-renal tubule polymerase chain reaction revealed marked reduction of mtDNA in COX-immunodeficient renal tubules. We conclude that adefovir-induced nephrotoxicity is mediated by depletion of mtDNA from proximal tubular cells through inhibition of mtDNA replication. This novel form of nephrotoxicity may serve as a prototype for other forms of renal toxicity caused by reverse transcriptase inhibitors.
Topics: Acute Kidney Injury; Adenine; Adult; Antiviral Agents; Cytochrome-c Oxidase Deficiency; DNA, Mitochondrial; Dissection; Drug Therapy, Combination; Electron Transport Complex IV; HIV Infections; Humans; Immunoenzyme Techniques; Kidney Tubules, Proximal; Male; Micromanipulation; Mitochondria; Necrosis; Organophosphonates; Polymerase Chain Reaction; Succinate Dehydrogenase
PubMed: 11486172
DOI: 10.1053/hupa.2001.25586 -
Asian Journal of Surgery Apr 2023
Topics: Humans; Fanconi Syndrome; Spinal Fractures; Osteomalacia; Hypophosphatemia; Phosphorus Metabolism Disorders
PubMed: 36274000
DOI: 10.1016/j.asjsur.2022.09.140 -
ChemMedChem Sep 2018A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of...
A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC values ranging from 4.1 to 5.6 μm in HEK293 cell-based assays.
Topics: Adenine; Adenylyl Cyclases; Bacillus anthracis; Bordetella pertussis; Dose-Response Relationship, Drug; Enzyme Inhibitors; Molecular Structure; Organophosphonates; Structure-Activity Relationship
PubMed: 29968968
DOI: 10.1002/cmdc.201800332 -
Internal Medicine Journal Aug 2012
Topics: Adenine; Drug Administration Schedule; Fanconi Syndrome; Hepatitis B; Humans; Male; Middle Aged; Nephritis, Interstitial; Organophosphonates; Time Factors
PubMed: 22906032
DOI: 10.1111/j.1445-5994.2012.02854.x -
Biochemical Pharmacology Sep 2016Adefovir, an acyclic nucleotide reverse transcriptase inhibitor used to treat hepatitis B viral infection, is primarily eliminated renally through cooperation of...
BACKGROUND AND AIMS
Adefovir, an acyclic nucleotide reverse transcriptase inhibitor used to treat hepatitis B viral infection, is primarily eliminated renally through cooperation of glomerular filtration with active tubular transport. Nonalcoholic steatohepatitis is a variable in drug disposition, yet the impact on renal transport processes has yet to be fully understood. The goal of this study was to determine the effect of nonalcoholic steatohepatitis on the pharmacokinetics of adefovir in rats given a control or methionine and choline deficient diet to induce nonalcoholic steatohepatitis.
METHODS
Animals received a bolus dose of 7mg/kg (35μCi/kg) [(3)H] adefovir with consequent measurement of plasma and urine concentrations. Inulin clearance was used to determine glomerular filtration rate.
RESULTS
Methionine and choline deficient diet-induced nonalcoholic steatohepatitis prolonged the elimination half-life of adefovir. This observation occurred in conjunction with reduced distribution volume and hepatic levels of adefovir. Notably, despite these changes, renal clearance and overall clearance were not changed, despite markedly reduced glomerular filtration rate in nonalcoholic steatohepatitis. Alteration of glomerular filtration rate was fully compensated for by a significant increase in tubular secretion of adefovir. Analysis of renal transporters confirmed transcriptional up-regulation of Mrp4, the major transporter for adefovir tubular secretion.
CONCLUSIONS
This study demonstrates changes to glomerular filtration and tubular secretion that alter pharmacokinetics of adefovir in nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis-induced changes in renal drug elimination processes could have major implications in variable drug response and the potential for toxicity.
Topics: Adenine; Animals; Choline; Diet; Glomerular Filtration Rate; Kidney; Male; Methionine; Non-alcoholic Fatty Liver Disease; Organophosphonates; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Inhibitors
PubMed: 27381944
DOI: 10.1016/j.bcp.2016.07.001 -
PloS One 2016The high levels of genetic diversity shown by hepatitis B virus (HBV) are commonly attributed to the low fidelity of its polymerase. However, the rate of spontaneous...
The high levels of genetic diversity shown by hepatitis B virus (HBV) are commonly attributed to the low fidelity of its polymerase. However, the rate of spontaneous mutation of human HBV in vivo is currently unknown. Here, based on the evolutionary principle that the population frequency of lethal mutations equals the rate at which they are produced, we have estimated the mutation rate of HBV in vivo by scoring premature stop codons in 621 publicly available, full-length, molecular clone sequences derived from patients. This yielded an estimate of 8.7 × 10-5 spontaneous mutations per nucleotide per cell infection in untreated patients, which should be taken as an upper limit estimate because PCR errors and/or lack of effective lethality may inflate observed mutation frequencies. We found that, in patients undergoing lamivudine/adefovir treatment, the HBV mutation rate was elevated by more than sixfold, revealing a mutagenic effect of this treatment. Genome-wide analysis of single-nucleotide polymorphisms indicated that lamivudine/adefovir treatment increases the fraction of A/T-to-G/C base substitutions, consistent with recent work showing similar effects of lamivudine in cellular DNA. Based on these data, the rate at which HBV produces new genetic variants in treated patients is similar to or even higher than in RNA viruses.
Topics: Adenine; Drug Resistance, Viral; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Lamivudine; Male; Mutation; Organophosphonates; Polymorphism, Single Nucleotide
PubMed: 27649318
DOI: 10.1371/journal.pone.0163363 -
Randomized trial of lamivudine, adefovir, and the combination in HBeAg-positive chronic hepatitis B.Clinics and Research in Hepatology and... Dec 2012The aim of this study was to compare the efficacy of lamivudine or adefovir alone for 96 weeks versus initial treatment with the combination of lamivudine and adefovir... (Comparative Study)
Comparative Study Randomized Controlled Trial
The aim of this study was to compare the efficacy of lamivudine or adefovir alone for 96 weeks versus initial treatment with the combination of lamivudine and adefovir for 12 to 24 weeks followed by adefovir alone. One hundred and fifty patients with HBeAg-positive chronic hepatitis B were randomized equally to lamivudine and adefovir diprivoxil combination therapy (LA), lamivudine alone (L), or adefovir dipivoxil alone (A) in a multicenter randomized clinical trial. In the LA group, the earliest time for lamivudine discontinuation was 12 weeks and adefovir monotherapy was continued until 96 weeks. Groups L and A received monotherapies for 96 weeks. At 12 weeks, the decrease in HBV DNA, percentage of patients with negative HBV DNA, and ALT normalization rate for the LA group were comparable to those of group L, but superior to those of group A. At 24 weeks, the rates of negative HBV DNA and HBeAg seroconversion of group LA were significantly higher than the monotherapy groups. This superiority was subsequently preserved during the maintenance phase with adefovir monotherapy. Starting at 48 weeks, the mean HBV DNA level of group L increased over the 24-week level. In contrast, the A group's rates of virological response, biochemical response, and HBeAg seroconversion continued to improve. At week 96, the percentage of patients with undetectable DNA and HBe seroconversion of LA group (100%, 51%) was higher than that of L (66%, 21%) and A group (49%, 33%), while no significant difference was observed between the L and A groups. During the course of therapy, no lamivudine- or adefovir-resistance mutations were discovered in the LA group. Rates of adverse reactions were comparable between the three groups. Combination therapy with lamivudine and adefovir for 12 to 24 weeks followed by adefovir monotherapy significantly improved antiviral efficacy and reduced drug resistance without compromising safety and tolerability compared to either drug alone in HBeAg-positive chronic hepatitis B.
Topics: Adenine; Adult; Antiviral Agents; Drug Therapy, Combination; Female; Hepatitis B e Antigens; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors
PubMed: 23069315
DOI: 10.1016/j.clinre.2012.05.012 -
Journal of Clinical Pharmacology Oct 2007This study evaluated the effect of entecavir on the pharmacokinetics of adefovir and the effect of adefovir on the pharmacokinetics of entecavir using a fixed-sequence... (Clinical Trial)
Clinical Trial
This study evaluated the effect of entecavir on the pharmacokinetics of adefovir and the effect of adefovir on the pharmacokinetics of entecavir using a fixed-sequence crossover design in healthy adult subjects. Subjects received 10 mg of adefovir once daily on days 1 to 4, 1 mg of entecavir on days 5 to 14, and 1 mg of entecavir plus 10 mg of adefovir on days 15 to 24. Pharmacokinetic assessments were performed on days 4 and 24 for adefovir and on days 14 and 24 for entecavir. The geometric mean ratios (90% confidence interval) for area under the plasma concentration-time curve in 1 dosing interval, peak plasma concentration, and 24-hour postdose plasma concentration of entecavir when coadministered with adefovir and of adefovir when coadministered with entecavir were within the prespecified 0.80 to 1.25 no-effect range. Entecavir and adefovir were well tolerated when administered in combination. Therefore, the pharmacokinetic data generated in this study indicate that entecavir and adefovir can be coadministered without the need for dosage adjustment.
Topics: Adenine; Adolescent; Adult; Antiviral Agents; Area Under Curve; Cross-Over Studies; Drug Interactions; Female; Guanine; Humans; Male; Organophosphonates
PubMed: 17675455
DOI: 10.1177/0091270007304780