Cellular Pharmacology of D-d4FC, a Nucleoside Analogue Active against Drug-Resistant HIV

Abstract

The backbone of effective highly active antiretroviral therapy regimens for the treatment of HIV infections currently contains at least two nucleosides. Among the features that influence the potency of each component of a regimen and the overall efficacy of the combination are the cellular uptake and bioconversion of nucleoside analogues to their active triphosphate form, and the extent of possible interactions in these steps that might occur when more than one nucleoside is used in a regimen. D-d4FC (Reverset), a new cytidine analogue with the ability to inhibit many nucleoside-resistant viral variants, was examined for these parameters. In phytohemaglutinin-stimulated human peripheral blood mononuclear cells, D-d4FC was taken up in a rapid (8 h to 50% maximal value), saturable (plateau above 10 microM parent nucleoside concentration) process, resulting in levels of D-d4FC triphosphate that should provide potent antiviral activity against a variety of virus genotypes. Based on measurement of antiviral effects in cell culture, additive and in some cases, synergistic interactions were observed with protease inhibitors, non-nucleoside reverse transcriptase inhibitors or other nucleosides, including cytidine analogues.

Selection and Characterization of HIV-1 with a Novel S68 Deletion in Reverse Transcriptase

“…Both enzymatic assay and recombinant RT assay demonstrated similar fold increases in resistance with or without ATP. Thus, these data demonstrated that S68⌬ resulted in resistance to several clinically important nucleoside analogs but remained susceptible to ZDV, thus supporting the previously published cell-based studies (6,9,15,40).…”

Antiviral and Cellular Metabolism Interactions between Dexelvucitabine and Lamivudine

“…These findings are consistent with a previous report by Erickson-Viitanen et al and support the hypothesis that enzymes involved in the activation of DFC and 3TC are not rate limiting for the production of their 5Ј-TP metabolites (9). It is likely that this drug interaction occurs at the NTP levels with the HIV RT.…”

“…Taken together, these studies suggest that although 3TC and DFC are cytidine analogs activated by 2Ј-deoxycytidine kinase, they may be considered for combination therapy for the treatment of HIV infections, although a dose reduction for 3TC may be needed (9,20). It should be noted that FTC, a related nucleoside, is approved at a dose of 200 mg, which is 33% and 50% lower than the approved dose of 3TC for HIV and hepatitis B virus, respectively.…”

“…This goal can be achieved by a combination of highly active antiretroviral therapy, involving the use of agents from at least two distinct classes such as two nucleoside reverse transcriptase inhibitors (NRTI) and either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (2,9). However, to date, the combination of two NRTI has been restricted to those nucleosides that are activated by different kinases in their first phosphorylation step (Fig.…”

Nucleoside and nucleotide inhibitors of HIV-1 replication

“…In vitro cell culture experiments suggested that the antiviral effects of reverset are additive and in some cases synergistic with PIs, NNRTIs and NRTIs [221]. Reverset is active against HIV-1 strains resistant to AZT, 3TC, d4T and tenofovir [218], as well as strains coresistant to AZT and 3TC and several strains bearing double and triple mutations [220].…”