HIV-1 resistance profile of the novel nucleoside reverse transcriptase inhibitor beta-D-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (Reverset)

Antivir Chem Chemother. 2003 Jan;14(1):49-59. doi: 10.1177/095632020301400105.


Nucleoside reverse transcriptase inhibitors (NRTIs) represent the cornerstone of highly active antiretroviral therapy when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or HIV-1 protease inhibitors (PIs). Unlike the NNRTIs and PIs, NRTIs must be successively phosphorylated by cellular kinases to a triphosphate form, which represents the active metabolite possessing antiviral activity. Emergence of viral resistance to NRTIs has severely hampered treatment options for persons infected with HIV-1. As such, there is an urgent need to develop NRTIs capable of suppressing NRTI-resistant strains of HIV-1. We have recently reported that the cytidine analogue D-d4FC (DPC817, Reverset) effectively inhibits clinically prevalent resistant strains of HIV-1. In this report, we have extended these findings and now describe a detailed resistance profile for this novel NRTI. By examining a panel of 50 viruses carrying RTs derived from HIV-1 clinical isolates displaying a wide range of NRTI resistance mutations, we report that the median fold increase in effective antiviral concentration for such a panel of viruses is 3.2, which is comparable to tenofovir (2.8-fold) and didanosine (2.4-fold). D-d4FC is highly effective at inhibiting subsets of lamivudine- and zidovudine-resistant variants but, like other NRTIs, seems less potent against multi-NRTI-resistant viruses, particularly those carrying the Q151M complex of mutations. Finally, in vitro selections for HIV-1 mutants capable of replicating in the presence of D-d4FC yielded a mutant carrying the RT K65R mutation. This mutation confers 5.3- to 8.7-fold resistance to D-d4FC in vitro. These findings suggest that D-d4FC may represent an alternative NRTI for the treatment of individuals infected with lamivudine- and zidovudine-resistant strains of HIV-1.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Cytidine Triphosphate / analogs & derivatives
  • Cytidine Triphosphate / analysis
  • Cytidine Triphosphate / pharmacology*
  • Didanosine / pharmacology
  • Drug Resistance, Multiple, Viral* / genetics
  • Genotype
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / isolation & purification
  • Humans
  • Lamivudine / pharmacology
  • Mutation
  • Organophosphonates*
  • Organophosphorus Compounds / pharmacology
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Species Specificity
  • Tenofovir
  • Transfection
  • Zalcitabine / analogs & derivatives
  • Zidovudine / pharmacology


  • Anti-HIV Agents
  • Organophosphonates
  • Organophosphorus Compounds
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • Zidovudine
  • Cytidine Triphosphate
  • Zalcitabine
  • Tenofovir
  • HIV Reverse Transcriptase
  • Adenine
  • Didanosine
  • dexelvucitabine