Dr. Dimachkie, Director of the Neuromuscular Disease Division and Executive Vice Chairman for Research Programs, Department of Neurology, The University of Kansas Medical Center, received honorariums from Alnylam, Audentes, Baxalta, Catalyst, CSL Behring, Mallinckrodt, Momemta, Novartis, NuFactor, Sanofi, Shire, RMS Medical, and Terumo for speaking engagements or consulting work, and grants from Alexion, Alnylam, Amicus, Biomarin, Catalyst, CSL Behring, FDA/OPD, Genentech, GlaxoSmithKline, Grifols, MDA Pharmaceuticals, NIH, Novartis, Octapharma, Orphazyme, Sanofi, UCB BioPharma, and Viromed.)
Dr. Weimer of Columbia University has received consulting fees from Roche.)
Historical note and terminology
Antiviral nucleoside analogues are a class of compounds that resemble natural nucleotide bases. When phosphorylated, they compete with endogenous nucleotides for binding to reverse transcriptase and cause termination of viral DNA chain elongation. Thus, they are potent inhibitors of the early phase of both HIV-1 and HIV-2 replication. Their individual use, or use in combination therapy, in patients with AIDS and AIDS-related complex has been associated with rapid suppression of serum p24 antigen levels, reduced infectious HIV titers in mononuclear cells, increases in CD4+ cell counts, and in some studies, improvement in the patient's reported quality of life (Yarchoan et al 1988; Merigan and Skowron 1990; Moyle et al 1993; Riddler and Anderson 1995; Fischl et al 1997; Rouleau et al 1997; Kelleher et al 1999). In the past decade, multiple antiviral nucleoside analogues have been developed and tested in vivo and in vitro, including: zalcitabine (ddC), didanosine (ddI), stavudine (d4T), and lamivudine (3TC). Each of these compounds has been associated with a dose-dependent, distal sensory polyneuropathy, which often exacerbates the common disorders of peripheral nerves that are associated with HIV disease. For many patients, peripheral neuropathy is the dose-limiting side effect associated with antiviral nucleoside analogue therapy (Moyle and Sadler 1998). Telbivudine (LdT) is a highly specific and potent synthetic thymidine nucleoside analogue. LdT inhibits hepatitis B virus (HBV) DNA polymerase, thereby interfering with hepatitis B viral replication. According to the package insert, peripheral neuropathy was reported as an adverse event in less than 1% of subjects receiving LdT monotherapy, whereas coadministration of LdT with pegylated interferon alfa-2a increases the risk and severity of peripheral neuropathy. More information can be accessed at:http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022011s013lbl.pdf.
Peak plasma concentration of antiviral nucleoside analogues generally occur 1 to 2 hours following oral administration (Rana and Dudley 1997), with bioavailability in adults ranging from 40% to 88% (Balis et al 1992; Whittington and Brogden 1992). Concentration in the CSF is approximately 20% of that in the plasma of adults, but the concentration is variable in children. Antiviral nucleoside analogues enter cells either with the aid of nucleoside carriers or by non-facilitated diffusion. The major route of excretion is renal, with approximately 70% of the compounds found unchanged in urine following intravenous dosing.
Therapeutic regimens for the treatment of HIV have stressed polypharmacy, combining various antiviral nucleoside analogues with each other and with protease inhibitors. Preliminary studies suggest that the pharmacokinetic properties of zalcitabine are not significantly altered by combination with other antiviral nucleoside analogues, as judged by peak serum concentrations, area under the plasma concentration-time curve, and serum half-life (Meng et al 1992; Rana and Dudley 1997). However, concentrations of didanosine have been reported to increase by 50% or more when coadministered with another antiviral nucleoside analogue (Taburet and Singlas 1996). The pharmacodynamic, pharmacokinetic, and neurotoxic properties of antiviral nucleoside analogues used in combination with other putative therapies remain to be fully explored.
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