Antiviral therapy: nucleotide and nucleoside analogs

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Goals of therapy

The goals of therapy for the management of HBV infection include the reduction in hepatic inflammation, normalization of serum ALT, and clearance of viremia; seroconversion from hepatitis B e antibody (HBeAg) to hepatitis B surface antibody (HBeAb) and ultimately loss of HBsAg with seroconversion to HBsAb. Improvement in necroinflammation in the liver decreases fibrosis, lessens the risk of progression to cirrhosis or HCC, and improves survival. However, endpoints of therapy, which have been

Viral replication

After the HBV viral particle enters the hepatocyte (by unclear receptors), it moves to the nucleus where the partially double-stranded DNA virus is repaired to form covalently closed circular DNA (cccDNA) [5]. It is unclear how much current therapies directly decrease cccDNA. HBV DNA is transcribed by host RNA polymerase and RNA is translated in the cytoplasm. RNA packaging and encapsidation occurs to form pregenomic RNA. This is the substrate on which HBV DNA polymerase acts by reverse

Lamivudine

Lamivudine, (-)-β-L-2′, 3′-dideoxy, 3′-thiacytidine (3TC) is a synthetic dideoxy analog of cytidine. Lamivudine exhibits antiviral activity against human immunodeficiency virus type 1 (HIV-1) and 2 (HIV-2) and HBV. Lamivudine is not active against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), influenza virus, respiratory syncytial virus (RSV), or varicella-zoster virus (VZV) [6], [7]. Similar to other nucleoside antiviral agents (eg,

Resistance to lamivudine

Unfortunately suppression of HBV DNA is not sustained in an increasing proportion of lamivudine-treated patients over time. Seen as early as after 6 months of continuous lamivudine therapy, YMDD mutations emerge. These are substitutions (methionine to valine or isoleucine) at position 204 in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of the C domain of HBV DNA polymerase. The incidence of these mutations increases with increasing treatment duration, from 16% to 32% at 1 year to

Adefovir

Adefovir dipivoxil (Hepsera, Gilead Sciences, Foster City, California) is an ester prodrug of adefovir [9-(2-phosphonylmethoxyethyl)adenine (PEMA)], a nucleotide analog of adenosine monophosphate. Nucleoside analogs such as acyclovir and ganciclovir must first be phosphorylated to their monophosphate forms by viral kinases and then further phosphorylated to their active triphosphate forms. Mutations in the viral kinases that prevent the conversion of these nucleoside analogs to their

Emtricitabine

Emtricitabine (Emtriva, Gilead Sciences), (-)-β-2′-3′-dideoxy-5-fluoro-3′-thiacytidine [1-β-L-FTC] is the (−) enantiomer thio analog of cytidine with a fluorine atom in the 5-position. Emtricitabine has activity against HBV and HIV-1. Emtricitabine is FDA approved for the treatment of HIV-1 infection, and is undergoing phase III clinical trials for the treatment of HBV infection. Emtricitabine is intracellularly phosphorylated to emtricitabine 5′-triphosphate (1-β-L-FTC-TP) and inhibits HBV DNA

Entecavir

Entecavir is a carbocyclic analog of 2′-deoxyguanosine with selective activity against HBV. Entecavir is not active against HIV, infuenza virus, CMV, HSV, or VZV [44]. Entecavir is phosphorylated to the active triphosphate form and competes with the substrate dGTP to inhibit HBV polymerase activity. Entecavir triphosphate blocks HBV replication by three mechanisms: (1) inhibiting the priming of HBV-DNA polymerase, (2) inhibiting the reverse transcription of the negative strands of HBV-DNA from

Telbivudine

Telbivudine, 2′-deoxy-L-thymidine (LdT) is a nucleoside analog that differs from the deoxynucleoside, thymidine by being in the β-L configuration compared with the naturally occurring β-D enantiomer [54]. The hydroxyl group at the 3′ position on the sugar moiety confers selective activity against hepadnaviruses. Telbivudine lacks activity against HIV, HSV, CMV, EBV, RSV, adenovirus, rhinovirus, influenza virus, and parainfluenza virus [55]. Telbivudine is converted to the active 5′ triphosphate

Clevudine

The nucleoside analog, Clevudine, (L-FMAU, 1-(2-fluoro-5-methyl-β,l-arabinofuranosyl) uracil) is a pyrimidine analog of the L-nucleoside family. It is active against EBV, HBV, and duck HBV replication in cell culture [59], [60]. L-FMAU is orally bioavailable with once-daily administration. It is a substrate for human thymidine kinase and human deoxycytidine kinase. It is active against woodchuck hepatitis virus [58], [61] and is in phase I/II study in humans.

Elvucitabine

Elvucitabine, 2′,3′-Dideoxy-2′3′-didehydro-β-L(−)5-fluorocytidine (β-L-Fd4C) is a β-L nucleoside analog with potent activity against HBV and HIV. It is currently undergoing phase II clinical trials evaluating safety and efficacy in HBV infection. β-L-Fd4C-triphosphate inhibits HBV DNA polymerase by competing with dCTP and is approximately 15 times more potent than lamivudine [62]. The elimination half-life of elvucitabine is approximately 4 hours, but the intracellular half-life of

Tenofovir

Tenofovir disoproxil fumarate (Viread, Gilead Sciences) is an ester prodrug of tenofovir. Tenofovir is an acyclic nucleoside phosphonate analog of adenosine-monophosphate. Tenofovir disoproxil fumarate is first hydrolyzed to tenofovir, then phosphorylated to the active diphosphate form. Tenofovir diphosphate inhibits HBV DNA polymerase by competing with deoxyadenosine triphosphate (dATP) for incorporation into nascent DNA, resulting in premature chain termination. Tenofovir has activity against

Valtorcitabine

Valtorcitabine, β-L-2-deoxycitidine (val-LdC) is selective inhibitor of HBV replication. LdC has no in vitro antiviral activity against HIV, RSV, HSV, VZV, CMV, or EBV. LdC in combination with LdT appears to be synergistic in vitro [44]. In a phase I/II trial, 200 mg/day of val-LdC resulted in a reduction of HBV DNA by as much as 2.7 log10. No serious or dose-related adverse effects were reported [67].

Summary

For the management of HBV infection, an increasing number of nucleotide and nucleoside analogs are active against wild-type HBV and some against HBV with YMDD and other compensatory mutations. Table 2 depicts the IC50 and susceptibilities of HBV to various antiviral agents. The dichotomy between in vitro and in vivo susceptibilities to YMDD mutants is due to a change in IC50 between wild-type and mutant virus. Thus a drug may have less activity in vitro but at doses used in vivo show activity

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References (70)

  • F Nevens et al.

    Lamivudine therapy for chronic hepatitis B: A six-month randomized dose-ranging study

    Gastroenterology

    (1997)
  • M.G Peters et al.

    Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B

    Gastroenterology

    (2004 Jan)
  • E.R Schiff et al.

    Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients

    Hepatology

    (2003 Dec)
  • P Angus et al.

    Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase

    Gastroenterology

    (2003)
  • L.T Martin et al.

    Effect of stereoisomerism on the cellular pharmacology of beta-enantiomers of cytidine analogs in Hep-G2 cells

    Biochem Pharmacol

    (1997)
  • B Seigneres et al.

    Inhibitory activity of dioxolane purine analogs on wild-type and lamivudine-resistant mutants of hepadnaviruses

    Hepatology

    (2002 Sep)
  • C.L Lai et al.

    Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection

    Gastroenterology

    (2002)
  • C.L Lai et al.

    Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection

    Gastroenterology

    (2002 Dec)
  • S.F Peek et al.

    Antiviral activity of clevudine [L-FMAU, (1-(2-fluoro-5-methyl-beta, L-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax)

    Hepatology

    (2001)
  • R.P Perrillo et al.

    A randomized, controlled trial of interferon ALFA-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B

    N Engl J Med

    (1990)
  • R McKenzie et al.

    Hepatic failure and lactic acidosis due to fialuridine (FIAU): an investigational nucleoside analogue for chronic hepatitis B

    N Engl J Med

    (1995)
  • S.L Doong et al.

    Inhibition of the replication of hepatitis B virus in vitro by 2′,3′-dideoxy-3′-thiacytidine and related analogues

    Proc Natl Acad Sci USA

    (1991)
  • A Severini et al.

    Mechanism of inhibition of duck hepatitis B virus polymerase by (-)-beta-L-2′,3′-dideoxy-3′-thiacytidine

    Antimicrob Agents Chemother

    (1995)
  • G Birkus et al.

    Comparative effects of adefovir and selected nucleoside inhibitors of hepatitis B virus DNA polymerase on mitochondrial DNA in liver and skeletal muscle cells

    J Viral Hepat

    (2003)
  • M.A Johnson et al.

    Clinical pharmacokinetics of lamivudine

    Clin Pharmacokinet

    (1999)
  • J.L Dienstag et al.

    Lamivudine as initial treatment for chronic hepatitis B in the United States

    N Engl J Med

    (1999)
  • C.L Lai et al.

    A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group

    N Engl J Med

    (1998)
  • A.B van Nunen et al.

    Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase

    Gut

    (2003)
  • Y Benhamou et al.

    Effects of lamivudine on replication of hepatitis B virus in HIV-infected men

    Ann Intern Med

    (1996)
  • M.I Allen et al.

    Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group

    Hepatology

    (1998)
  • S.K Ono-Nita et al.

    Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors

    J Clin Invest

    (1999)
  • W.E Delaney et al.

    In vitro cross-resistance testing of Adefovir, entecavir, and b-L-thymidine (L-DT) against drug-resistant strains of HBV [Abstract]

    Hepatology

    (2001)
  • Y.F Liaw

    Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy

    Hepatology

    (1999)
  • X Xiong et al.

    Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro [see comments]

    Hepatology

    (1998)
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