Disease relevance of D01655

• CONTEXT: Adefovir dipivoxil is a nucleotide analog that has demonstrated effective antiretroviral activity against human immunodeficiency virus (HIV) with once-daily administration [1].
• Long-term Therapy With Adefovir Dipivoxil for HBeAg-Negative Chronic Hepatitis B for up to 5 Years [2].
• BACKGROUND & AIMS: Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B [3].
• INTERPRETATION: These results indicate that 48 weeks of 10 mg daily adefovir dipivoxil is well tolerated and active against lamivudine-resistant HBV in HIV-1/HBV co-infected patients [4].
• Conclusions: Treatment with adefovir dipivoxil for up to 240 weeks was well tolerated and produced significant, increasing improvement in hepatic fibrosis, durable suppression of HBV replication, normalization of liver enzymes, and delayed development of resistance [2].

High impact information on D01655

• Background & Aims: Treatment with adefovir dipivoxil for 48 weeks resulted in clinical improvement in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B that was lost when treatment was discontinued [2].
• We evaluated the efficacy and safety of adding adefovir dipivoxil to lamivudine in 135 patients with chronic hepatitis B (CHB) and YMDD mutant HBV [5].
• CONCLUSIONS: The development of this novel mutation in the HBV polymerase confers resistance to adefovir dipivoxil [3].
• We therefore analyzed the frequency and distribution of genotypes in patients from 2 multinational phase III studies of adefovir dipivoxil [6].
• Adefovir dipivoxil was generally well tolerated, but was associated with a transient increase in serum alanine aminotransferase concentrations in 15 patients [4].

Chemical compound and disease context of D01655

• Tenofovir disoproxil fumarate (TDF) and adefovir dipivoxil (ADV) are licensed for the treatment of HIV-1 and HBV infection, respectively, but both have in vivo and in vitro activity against HBV [7].
• The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection [8].
• A 48-week open-label study of 11 antiretroviral-naive, human immunodeficiency virus type 1 (HIV-1)-infected adults evaluated once-daily treatment with adefovir dipivoxil, lamivudine, didanosine, and efavirenz [9].
• Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegalovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread) [10].
• The aim of our study was to determine whether treatment with adefovir, a new acyclic nucleoside phosphonate, the prodrug of which, adefovir dipivoxil, is in clinical evaluation, is able to suppress viral CCC DNA both in vitro and in vivo using the duck HBV (DHBV) model [11].

Biological context of D01655

• Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy [12].
• By reducing the rate and frequency of development of drug resistance, adefovir dipivoxil and other new oral antiviral agents maximize the clinical advantages of long-term sustained viral suppression (HBV DNA reduction) to achieve lasting therapeutic benefits [13].
• Pharmacokinetic experiments with mice showed that the oral bioavailabilities of PMEA following oral gavage of bis(POM)-PMEA, diphenyl-PMEA, or PMEA (at a dose equivalent to 50 mg of PMEA per kg) were 53,3, and 16%, respectively [14].
• Antiviral efficacy and pharmacokinetics of oral adefovir dipivoxil in chronically woodchuck hepatitis virus-infected woodchucks [15].
• No serious adverse events related to adefovir dipivoxil occurred during the study, and HIV-1 RNA and CD4+ cell counts were stable [16].

Anatomical context of D01655

• We have found that adefovir dipivoxil, a drug approved to treat chronic infection of hepatitis B virus, effectively inhibits EF-induced cAMP accumulation and changes in cytokine production in mouse primary macrophages [17].
• GI disturbances, hepatic effects and delayed renal abnormalities are the principal adverse events seen with adefovir dipivoxil [18].
• At week 6, changes in absolute CD4 T cell levels and HIV-1 RNA levels were significantly greater with adefovir dipivoxil than with placebo [19].
• The effect of the acyclic nucleotide analogue, 9-(2-phosphonomethoxyethyl)adenine (PMEA, Adefovir), and its (bis)pivaloyloxymethyl ester (bis-POM-PMEA, Adefovir Dipivoxil) on in vitro nitric oxide (NO) production by murine peritoneal macrophages was investigated [20].
• Effective phosphorylation coupled with a long intracellular half-life and small competing dATP pool sizes in primary hepatocytes forms the cellular metabolic basis for the efficacy of adefovir dipivoxil in the treatment of chronic hepatitis B [21].

Associations of D01655 with other chemical compounds

• Drug-resistant mutations affecting other regions of HBV polymerase have also been reported, but at much lower rates in patients who have received adefovir dipivoxil or entecavir [22].
• Unlike lamivudine, adefovir dipivoxil, an oral anti-HBV agent in late-stage development, has not been associated with HBV resistance, either in vitro or in vivo [13].
• Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects [8].
• Lamivudine has recently received approval for clinical use against chronic human HBV infection, and both PCV and PMEA have undergone clinical trials against HBV in their respective prodrug forms (famciclovir and adefovir dipivoxil [bis-(POM)-PMEA]) [23].
• Efavirenz- and adefovir dipivoxil-based salvage therapy in highly treatment-experienced patients: clinical and genotypic predictors of virologic response [24].

Gene context of D01655

• MRP4 also rendered resistance to adefovir dipivoxil (bis-POM-PMEA) and methotrexate, two reported MRP4 substrates [25].
• Genotypic analyses of samples from patients enrolled in a phase I/II clinical trial of adefovir dipivoxil demonstrated that the K70E RT mutation developed in two of 29 patients during extended therapy [26].
• Oral bis(POM)-PMEA afforded anti-MSV efficacy equal to that of subcutaneous PMEA given at equimolar doses [14].
• Current treatment options for patients with HBV-related cirrhosis include interferon-alpha (IFN-alpha), lamivudine and adefovir dipivoxil [27].
• Enzymatic degradation of the prodrug by carboxylesterase was confirmed by incubation of bis(POM)-PMEA with purified enzyme (Km = 87 microM and Vmax = 9.5 microM/min) [28].

Analytical, diagnostic and therapeutic context of D01655

• To address this issue, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the number and functionality of circulating DCs was studied during 6 months of treatment [29].
• The therapeutic role of adefovir-dipivoxil in acute de novo HBV infection after transplantation is uncertain [30].
• Favourable outcome of adefovir-dipivoxil treatment in acute de novo hepatitis B after liver transplantation [30].
• Also, the recoveries of free PMEA in the urine upon oral administration of bis(POM)-PMEA, diphenyl-PMEA, or PMEA (at a dose equivalent to 25 mg of PMEA per kg) were 48, 4, and 7%, respectively [14].
• Adefovir dipivoxil 60mg was as effective as 120mg (both once daily) after 20 weeks' treatment in a randomised double-blind study in antiretroviral-experienced (protease inhibitor-naive) patients [18].

References