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Journal of Gastroenterology and... Jan 2015Suboptimal viral suppression with adefovir (ADV) poses a challenge in managing chronic hepatitis B. Few studies have evaluated the efficacy of entecavir (ETV) in...
BACKGROUND AND AIM
Suboptimal viral suppression with adefovir (ADV) poses a challenge in managing chronic hepatitis B. Few studies have evaluated the efficacy of entecavir (ETV) in ADV-experienced patients. Our aim is to assess treatment effectiveness of ETV in ADV-experienced patients.
METHODS
ADV-experienced patients switched to ETV were enrolled from six US clinics. Patients completed a median of 24 months of ETV after switch. Patients were categorized into partial responders (detectable HBV-DNA at switch) or complete responders (undetectable HBV-DNA at switch) to ADV. Primary and secondary outcome measurements were complete viral suppression (CVS, HBV-DNA < 60 IU/mL) and biochemical response (BR, alanine aminotransferase [ALT] < 40 U/L), respectively.
RESULTS
A total of 120 patients were included in the analysis (80 ADV partial responders; 40 ADV complete responders). In partial responders, CVS rate was 84% after 24 months of ETV. BR rate was 58% at switch to ETV and increased to 90% after 24 months. All complete responders continued to experience CVS after switch. On multivariate analysis inclusive of age, male gender, ALT level at switch, and history of lamivudine (LAM) exposure, we identified positive, hepatitis B e antigen status before ADV and higher HBV-DNA level at time of switch as significant independent negative predictors of CVS. In eight patients with ADV resistance, seven achieved CVS after 24 months of ETV, and all achieved BR.
CONCLUSION
In ADV-experienced patients, high rates of CVS and BR can be achieved/sustained after switching to ETV, including those with ADV resistance or with prior exposure to LAM.
Topics: Adenine; Adult; Alanine Transaminase; Antiviral Agents; Biomarkers; Drug Substitution; Female; Follow-Up Studies; Hepatitis B, Chronic; Humans; Lamivudine; Male; Middle Aged; Multivariate Analysis; Organophosphonates; Time Factors; Treatment Outcome; Viral Load
PubMed: 25168842
DOI: 10.1111/jgh.12728 -
The Brazilian Journal of Infectious... 2012The results of several new clinical trials that compared the effectiveness of entecavir (ETV) treatment with that of adefovir (ADV) treatment in patients with chronic... (Comparative Study)
Comparative Study Meta-Analysis
The results of several new clinical trials that compared the effectiveness of entecavir (ETV) treatment with that of adefovir (ADV) treatment in patients with chronic hepatitis B (CHB) were published in recent years. However, the numbers of patients included in these clinical trials were too small to draw a clear conclusion as to whether ETV is more effective than ADV. Therefore, a new meta-analysis was needed to compare ETV with ADV for the treatment of CHB. A search of the Cochrane Central Register of Controlled Trials (CCTR), MEDLINE, the Science Citation Index, Embase, the China National Knowledge Infrastructure (CNKI), and the Wanfang Database for relevant studies published between 1966 and 2010 was performed. Trials comparing the use of ETV and ADV for the treatment of CHB were assessed. Of the 2,358 studies screened, 13 randomized controlled clinical trials comprising 1,230 patients (ETV therapy, 621; ADV therapy, 609) were analyzed. The serum hepatitis B virus (HBV) DNA clearance rate obtained in patients treated with ETV was significantly higher than that in patients treated with ADV at the 24th and 48th weeks of treatment (24 weeks: 59.6% vs. 31.8%, relative risk [RR], 1.82, 95% CI: 1.49-2.23; 48 weeks: 78.3% vs. 50.4%, RR, 1.61, 95% CI: 1.32-1.96). The serum HBeAg clearance rate, the HBeAg seroconversion rate, and the ALT normalization rate obtained for patients treated with ETV were also higher than the corresponding values for patients treated with ADV at the 48th week of treatment. The safety profiles were similar between patients treated with ETV and those treated with ADV. The evidence reviewed in this meta-analysis suggests that patients with hepatitis B have a greater likelihood of achieving a viral response and a biomedical response when treated with ETV than when treated with ADV.
Topics: Adenine; Antiviral Agents; Guanine; Hepatitis B, Chronic; Humans; Organophosphonates; Randomized Controlled Trials as Topic
PubMed: 22846126
DOI: 10.1016/j.bjid.2012.06.016 -
BMC Nephrology Aug 2017An increasing number of case reports suggest that acquired renal Fanconi syndrome may be associated with prolonged use of adefovir against hepatitis B virus. Renal...
BACKGROUND
An increasing number of case reports suggest that acquired renal Fanconi syndrome may be associated with prolonged use of adefovir against hepatitis B virus. Renal Fanconi syndrome is an uncommon disease, and its complication with nephrolithiasis is quite rare. Herein, we report a rare coexistence of nephrolithiasis and acquired renal Fanconi syndrome in a chronic hepatitis B-positive patient with prolonged adefovir therapy.
CASE PRESENTATION
The patient presented with osteomalacia and nephrolithiasis. Consequently, extracorporeal shock-wave lithotripsy and left double-J ureteral stent insertion were considered for obstructive nephropathy, which was caused by nephrolithiasis. However, osteomalacia had been misdiagnosed as osteoporosis before admission to our hospital. On admission, a complexity of multiple fractures, hypophosphataemia, glycosuria without hyperglycaemia and non-anion-gap metabolic acidosis indicated a diagnosis of acquired renal Fanconi syndrome induced by adefovir. After switching from adefovir to entecavir, the patient's symptoms and laboratory findings improved significantly.
CONCLUSIONS
The mechanism responsible for nephrolithiasis in renal Fanconi syndrome is still unclear. We recommend regularly monitoring renal function and serum calcium and serum phosphate to prevent renal Fanconi syndrome during the prolonged use of adefovir for hepatitis B virus.
Topics: Adenine; Antiviral Agents; Fanconi Syndrome; Hepatitis B; Humans; Male; Middle Aged; Nephrolithiasis; Organophosphonates; Osteomalacia
PubMed: 28851305
DOI: 10.1186/s12882-017-0693-4 -
GMHC Treatment Issues : the Gay Men's... Feb 1996
Clinical Trial
Topics: Adenine; Antiviral Agents; Biological Availability; CD4 Lymphocyte Count; Humans; Organophosphonates; Reverse Transcriptase Inhibitors
PubMed: 11363385
DOI: No ID Found -
Toxicology in Vitro : An International... Feb 2015Lack of in vitro to in vivo translation is a major challenge in safety prediction during early drug discovery.One of the most common in vitro assays to evaluate the...
Lack of in vitro to in vivo translation is a major challenge in safety prediction during early drug discovery.One of the most common in vitro assays to evaluate the probability of a compound to cause adverse effects is a cytotoxicity assay. Cytotoxicity of a compound is often measured by dose–response curves assuming the administered doses and intracellular exposures are equal at the time of measurement.However, this may not be true for compounds with low membrane permeability or those which are substrates for drug transporters as intracellular concentrations are determined both by passive permeability and active uptake through drug transporters. We show here that three antiviral drugs, adefovir, cidofovir and tenofovir exhibit significantly increased cytotoxicity in HEK293 cells transfected with organic anion transporter (OAT) 1 and 3 compared to a lack of cytotoxicity in HEK293 wildtype cells. A further look at the media and intracellular drug concentrations showed that 24 h after dosing, all three drugs had higher intracellular drug concentrations than that of media in the HEK-OAT1 cells whereas the intracellular drug concentrations in the wildtype cells were much lower than the administered doses. Comparing cytotoxicity IC(50) values of adefovir, cidofovir and tenofovir based on administered doses and measured intracellular concentrations in HEK-OAT1 cells revealed that intracellular drug concentrations have significant impact on calculated IC(50) values. Tenofovir showed much less intrinsic cytotoxicity than adefovir and cidofovir using intracellular concentrations rather than media concentration. Our data suggest that for low permeable drugs or drugs that are substrates for drug transporters, the choice of cellular model is critical for providing an accurate determination of cytotoxicity.
Topics: Adenine; Antiviral Agents; Cidofovir; Cytosine; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Organic Anion Transport Protein 1; Organophosphonates; Tenofovir; Toxicity Tests
PubMed: 25448811
DOI: 10.1016/j.tiv.2014.10.019 -
Journal of Clinical Virology : the... Apr 2006We describe a case of severe reactivation of occult hepatitis B virus infection in a 49-year-old man, who was treated with high doses of chlorambucil for a Binet stage A...
We describe a case of severe reactivation of occult hepatitis B virus infection in a 49-year-old man, who was treated with high doses of chlorambucil for a Binet stage A B-cell chronic lymphocytic leukemia (B-CLL). The patient was initially treated with lamivudine and subsequently with lamivudine and adefovir dipivoxil combination therapy to control viral replication and allow for long-term anti-cancer chemotherapy with alemtuzumab (Campath-1H), which was introduced to rescue for a B-CLL relapse. During 20 months of anti-HBV therapy, ALT and HBV-DNA levels progressively declined and B-CLL was successfully kept under control by long-term alemtuzumab administration.
Topics: Adenine; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Antiviral Agents; Drug Therapy, Combination; Hepatitis B; Humans; Lamivudine; Leukemia, Lymphocytic, Chronic, B-Cell; Organophosphonates; Recurrence; Treatment Outcome
PubMed: 16316778
DOI: 10.1016/j.jcv.2005.10.009 -
Advances in Pharmacology (San Diego,... 2013The Holý Trinity was named after Dr Antonín Holý (the Holý Trinity being an Unesco recognized monument in Olomouc, Czech Republic), who together with Dr John C.... (Review)
Review
The Holý Trinity was named after Dr Antonín Holý (the Holý Trinity being an Unesco recognized monument in Olomouc, Czech Republic), who together with Dr John C. Martin (Gilead Sciences) and myself pioneered a new class of antiviral agents, the acyclic nucleoside phosphonates. These compounds have revolutionized the antiviral drug field with several drugs that have been approved for the treatment of various DNA virus infections (cidofovir), hepatitis B (adefovir), and AIDS (HIV infection; tenofovir). The latter is also available as its oral prodrug, tenofovir disoproxil fumarate, for the treatment of hepatitis B and in combination with emtricitabine ((-)FTC) for the treatment and prophylaxis of HIV infections and in combination with (-)FTC and other HIV inhibitors, that is, efavirenz, rilpivirine, or elvitegravir (and a pharmacoenhancer thereof, cobicistat), for the treatment of AIDS.
Topics: Adenine; Antiviral Agents; Cidofovir; Cytosine; Drug Therapy, Combination; Humans; Nucleosides; Organophosphonates; Prodrugs; Tenofovir; Virus Diseases
PubMed: 23886004
DOI: 10.1016/B978-0-12-405880-4.00008-1 -
Hepatology (Baltimore, Md.) Dec 2005Progression of hepatitis B in patients with lamivudine-resistant strains is slowed down by adefovir dipivoxil (ADV). Whether the time point of ADV administration...
Progression of hepatitis B in patients with lamivudine-resistant strains is slowed down by adefovir dipivoxil (ADV). Whether the time point of ADV administration (genotypic vs. phenotypic resistance) influences the outcome of therapy is unknown. We compared the outcome of ADV therapy in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients with genotypic and phenotypic resistance to lamivudine. Ten milligrams of ADV was administered daily for 2 years to 46 HBeAg-negative patients at the time of phenotypic resistance (group A, >6 log(10) copies/mL of hepatitis B virus [HBV] DNA and high alanine aminotransferase [ALT] levels) and 28 patients at the time of genotypic resistance (group B, 3-6 log(10) copies/mL of HBV-DNA and normal ALT). HBV DNA was assessed every 2 months using Versant 3.0 assay, and lamivudine resistance was confirmed via INNO-LiPA assay in all patients. By month 3, HBV DNA tested negative in all patients from group B compared with only 20 (46%) in group A (P < .0001). The 2-year rates of virological response were 100% in the former patients and 78% in the latter ones (P < .0001). ALT levels remained persistently normal in all group B patients, whereas in group A patients they normalized at rates of 50% at month 6 (P < .0001), 72% at month 12 (P < .01), and 93% at month 24. None of the patients developed ADV resistance or ADV-related side effects. In conclusion, to optimize antiviral treatment in HBeAg-negative patients selecting resistant strains to lamivudine, ADV should be added to lamivudine as soon as genotypic resistance is detected.
Topics: Adenine; Adult; Aged; Alanine Transaminase; Antiviral Agents; DNA, Viral; Drug Resistance, Viral; Female; Genotype; Hepatitis B; Hepatitis B e Antigens; Hepatitis B virus; Humans; Lamivudine; Male; Middle Aged; Organophosphonates; Prospective Studies
PubMed: 16317671
DOI: 10.1002/hep.20939 -
Antimicrobial Agents and Chemotherapy Nov 1995The pharmacokinetics and bioavailability of adefovir [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels in three phase I/II studies in 28 human... (Clinical Trial)
Clinical Trial
The pharmacokinetics and bioavailability of adefovir [9-[2-(phosphonomethoxy)ethyl]adenine] were examined at two dose levels in three phase I/II studies in 28 human immunodeficiency type 1-infected patients. The concentrations of adefovir in serum following the intravenous infusion of 1.0 or 3.0 mg/kg of body weight were dose proportional and declined biexponentially, with an overall mean +/- standard deviation terminal half-life of 1.6 +/- 0.5 h (n = 28). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 12 h, and more than 98% was recovered by 24 h postdosing. The overall mean +/- standard deviation total serum clearance of the drug (223 +/- 53 ml/h/kg; n = 25) approximated the renal clearance (205 +/- 78 ml/h/kg; n = 20), which was significantly higher (P < 0.01) than the baseline creatinine clearance in the same patients (88 +/- 18 ml/h/kg; n = 25). Since adefovir is essentially completely unbound in plasma or serum, these data indicate that active tubular secretion accounted for approximately 60% of the clearance of adefovir. The steady-state volume of distribution of adefovir (418 +/- 76 ml/kg; n = 28) suggests that the drug was distributed in total body water. Repeated daily dosing with adefovir at 1.0 mg/kg/day (n = 8) and 3.0 mg/kg/day (n = 4) for 22 days did not significantly alter the pharmacokinetics of the drug; there was no evidence of accumulation. The oral bioavailability of adefovir at a 3.0-mg/kg dose was < 12% (n = 5) on the basis of the concentrations in serum or 16.4% +/- 16.0% on the basis of urinary recovery. The subcutaneous bioavailability of adefovir at a 3.0-mg/kg dose was 102% +/- 8.3% (n = 5) on the basis of concentrations in serum or 84.8% +/- 28.5% on the basis of urinary recovery. These data are consistent with preclinical observations in various species.
Topics: Adenine; Administration, Oral; Adult; Antiviral Agents; Biological Availability; Female; HIV Infections; HIV-1; Half-Life; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Organophosphonates; Protein Binding
PubMed: 8585716
DOI: 10.1128/AAC.39.11.2401 -
Journal of Medicinal Chemistry Feb 2008Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the...
Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were synthesized with the rationale that this selectively liver-activated prodrug class would enhance liver levels of the active metabolite adefovir diphosphate (ADV-DP) and/or decrease kidney exposure. The lead prodrug (14, MB06866, pradefovir), identified from a variety of in vitro and in vivo assays, exhibited good oral bioavailability (F = 42%, mesylate salt, rat) and rate of prodrug conversion to ADV-DP. Tissue distribution studies in the rat using radiolabeled materials showed that cyclic 1-aryl-1,3-propanyl prodrugs enhance the delivery of adefovir and its metabolites to the liver, with pradefovir exhibiting a 12-fold improvement in the liver/kidney ratio over adefovir dipivoxil.
Topics: Adenine; Administration, Oral; Animals; Biological Availability; Dogs; Hepatocytes; In Vitro Techniques; Liver; Male; Microsomes, Liver; Organophosphonates; Organophosphorus Compounds; Prodrugs; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution
PubMed: 18173234
DOI: 10.1021/jm7012216