Current treatment of hepatitis B virus infections

Clercq, Erik De

doi:10.1002/rmv.1849

Cited by 15 publications

(10 citation statements)

References 87 publications

(97 reference statements)

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“…To obtain clearance, a real "cure" of a chronic virus infection, as noted for HCV, is unheard of in the medical history of infectious diseases and sharply contrasts with the situation for HIV and HBV infections. In principle, current development of anti-HIV drugs requires lifelong treatments, while anti-HBV therapies may lead to a real cure only in a small percentage of HBV-infected patients (295,296).…”

Section: Hcv Ns5b Inhibitorsmentioning

confidence: 99%

Approved Antiviral Drugs over the Past 50 Years

2016

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SUMMARYSince the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2′-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2′-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide.

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Section: Hcv Ns5b Inhibitorsmentioning

confidence: 99%

Approved Antiviral Drugs over the Past 50 Years

2016

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“…Adefovir, an acyclic nucleotide reverse transcriptase inhibitor, is approved for the therapy of chronic hepatitis B, in adults with permanently increased serum alanine transaminase (ALT) activity, and histological evidence of active liver inflammation and fibrosis[1,2]. In addition to significant clinical efficacy against HBV infection, adefovir can be used during decompensated liver disease because it is dependent upon the renal processes of glomerular filtration and active tubular secretion for elimination[3,4].…”

Section: Introductionmentioning

confidence: 99%

Effect of nonalcoholic steatohepatitis on renal filtration and secretion of adefovir

Laho

Clarke

Dzierlenga

et al. 2016

Biochemical Pharmacology

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Background & 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 7 mg/kg (35 μCi/kg) [3H]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.

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“…The latter is a small-molecule medicine that was initially designed as an HIV treatment, but the clinical studies showed that absent targeted delivery to macrophages, therapeutically active doses of adefovir are unsafe for patients. As a result, its clinical applications are now limited to the low-dose format to treat a lower value target, hepatitis B virus [57]. Conjugation of adefovir to the Hp/Hb complex appears to be a reasonable strategy to achieve the desired therapeutic outcome with a lower drug dosage by virtue of targeted delivery.…”

Section: Icp-ms Detection Of Hp·hb Ga In Human Serummentioning

confidence: 99%

Evaluation of Gallium as a Tracer of Exogenous Hemoglobin–Haptoglobin Complexes for Targeted Drug Delivery Applications

Kaltashov

2016

J. Am. Soc. Mass Spectrom.

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Abstract. Haptoglobin (Hp) is a plasma glycoprotein that generates significant interest in the drug delivery community because of its potential for delivery of antiretroviral medicines with high selectivity to macrophages and monocytes, the latent reservoirs of human immunodeficiency virus. As is the case with other therapies that exploit transport networks for targeted drug delivery, the success of the design and optimization of Hp-based therapies will critically depend on the ability to accurately localize and quantitate Hp-drug conjugates on the varying and unpredictable background of endogenous proteins having identical structure. In this work, we introduce a new strategy for detecting and quantitating exogenous Hp and Hp-based drugs with high sensitivity in complex biological samples using gallium as a tracer of this protein and inductively coupled plasma mass spectrometry (ICP MS) as a method of detection. Metal label is introduced by reconstituting hemoglobin (Hb) with gallium(III)-protoporphyrin IX followed by its complexation with Hp. Formation of the Hp/Hb assembly and its stability are evaluated with native electrospray ionization mass spectrometry. Both stable isotopes of Ga give rise to an abundant signal in ICP MS of a human plasma sample spiked with the metallabeled Hp/Hb complex. The metal label signal exceeds the spectral interferences' contributions by more than an order of magnitude even with the concentration of the exogenous protein below 10 nM, the level that is more than adequate for the planned pharmacokinetic studies of Hp-based therapeutics.

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Current treatment of hepatitis B virus infections

Cited by 15 publications

References 87 publications

Approved Antiviral Drugs over the Past 50 Years

Approved Antiviral Drugs over the Past 50 Years

Effect of nonalcoholic steatohepatitis on renal filtration and secretion of adefovir

Evaluation of Gallium as a Tracer of Exogenous Hemoglobin–Haptoglobin Complexes for Targeted Drug Delivery Applications

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