Antiviral therapy: nucleotide and nucleoside analogs
Section snippets
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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2017, European Journal of Pharmaceutics and BiopharmaceuticsCitation Excerpt :The use of nucleoside analogues as antiviral agents mainly involves human immunodeficiency virus (HIV) (e.g. azidothymidine, stavudine, dideoxy-inosine and -cytidine) and herpes simplex virus treatment (e.g. acyclonucleosides) [31]. Research is also conducted on the application of these drugs in the treatment of hepatitis B [32] and hepatitis C [33] viral infections. Antiviral nucleoside analogues differ in terms of mechanism of action in comparison to orally available drugs, which target the viral polymerase.
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2011, Antiviral ResearchCitation Excerpt :Theoretically, compounds that interfere with any step in the HBV life cycle are likely to reduce the production of HBV. Recently, many small molecules such as nucleoside and nucleotide analogs (like lamivudine, adefovir, entecavir, telbivudine and tenofovir) that enter cells and inhibit HBV production by targeting the viral DNA polymerase are already being used clinically to treat HBV infection (Reynaud et al., 2009; Quan and Peters, 2004). Most recently, some nonnucleoside small molecules, which inhibit HBV replication by interfering with nucleocapsid assembly or encapsidation, were also reported (Deres et al., 2003; Feld et al., 2007; King et al., 1998; Stray and Zlotnick, 2006).
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2007, Archives of Medical ResearchCitation Excerpt :Treatment was well tolerated and no adverse events were present during the follow-up (26). This is a deoxyguanine nucleoside analog that inhibits HBV replication by a triple mechanism of action: it inhibits the priming of the DNA polymerase, inhibits the reverse transcription of the negative strands of DNA from the pre-genomic messenger RNA and inhibits the synthesis of the positive strand of DNA (27). Entecavir is effective in the treatment of wild-type as well as lamivudine-resistant HBV and reduces HBV DNA to a greater degree than lamivudine by virtue of its triple mechanism of action (28).
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