Mechanism of Action: Nucleoside reverse transcriptase inhibitor. Dexelvucitabine (DFC), a cytidine analog, is phosphorylated to its active 5′-triphosphate form, DFC-TP, which has an intracellular half-life of approximately 13 to 17 hours.5,6 DFC-TP inhibits the activity of HIV-1 reverse transcriptase by competing with natural substrates and causing DNA chain termination after incorporation into viral DNA.5,7
T½: 3.6 hours (single IV dose of dexelvucitabine in rhesus monkeys).5
Metabolism/Elimination: Animal studies suggest that dexelvucitabine is not significantly metabolized via glucuronidation. Dexelvucitabine is eliminated primarily by renal excretion when administered via the IV route. Following a single 33.3 mg/kg IV dose of dexelvucitabine in rhesus monkeys, 76% of the original dose was recovered intact in the urine within 8 hours of administration.8
Resistance: In vitro studies have demonstrated that dexelvucitabine maintains potency against HIV that is associated with zidovudine and/or lamivudine drug resistance, including NRTI-associated resistance caused by mutations M184V, M41L, D67N, K70R, T215Y, and K219Q. However, the K65R mutation was shown to confer 7- to 9-fold resistance to dexelvucitabine relative to wild-type virus.5 Additionally, in HIV-1LAI-infected primary human lymphocytes, dexelvucitabine can select for a novel deletion of the S68 codon in HIV-1 reverse transcriptase, which can occur independent of and before the K65R mutation arises or in combination with K65R mutation. In vitro drug susceptibility results indicate that HIV with the S68 deletion produces more than a 30-fold increase in resistance to dexelvucitabine and other NRTIs.6
In Study RVT-203, dexelvucitabine 200 mg once daily was shown to retain activity over 16 weeks in treatment-experienced participants, the majority of whom had multiple thymidine analog mutations. The most prevalent genotypes in this study were M41L/D67N/T215Y/F/K219Q/E ± M184V and M41L/L210W/T215Y/F ± M184V. Among participants with these genotypes, 41% of those taking dexelvucitabine 200 mg versus 30% of those taking placebo displayed a greater than 1-log decline in viral load after 16 weeks of therapy. The greatest antiviral activity was seen in participants taking dexelvucitabine 200 mg without concurrent lamivudine or emtricitabine; 71% of such participants had a greater than 1-log decline in viral load. In the presence of the K65R mutation, dexelvucitabine was active, while virus with Q151M was resistant to dexelvucitabine.9,10
In the Phase IIb trial (Study 203), adverse events were generally mild and included headache, fatigue, and gastrointestinal disorders. Grade 4 hyperlipasemia occurred in 34% of patients who were taking dexelvucitabine with didanosine. Among patients who were not receiving concurrent didanosine, asymptomatic grade 4 elevated lipase levels occurred in 5.4% of patients taking dexelvucitabine 200 mg versus 3.1% of patients taking placebo. Pancreatitis, resolving off treatment, occurred in three patients, all of whom were taking dexelvucitabine concurrently with didanosine and tenofovir DF.10
Grade 4 hyperlipasemia was also noted in Study 901, the long-term extension of Study 203. Because of an increasing incidence of grade 4 hyperlipasemia occurring in patients taking dexelvucitabine 200 mg without lamivudine or emtricitabine, the clinical development of dexelvucitabine for the treatment of HIV infection was discontinued.4
1. United States National Library of Medicine. ChemIDplus Advanced. Last accessed on November 30, 2013.
3. Incyte Corporation: Press Release, dated September 8, 2003. Incyte and Pharmasset Enter into a Collaborative Licensing Agreement for a Phase II HIV Drug. Last accessed on November 30, 2013.
4. Incyte Corporation: Press Release, dated April 3, 2006. Incyte to Discontinue Development of DFC as a Treatment for HIV; Conference Call Scheduled for 8:30 a.m. ET Today. Last accessed on November 30, 2013.
5. Schinazi RF, Mellors J, Bazmi H, et al. DPC 817: a cytidine nucleoside analog with activity against zidovudine- and lamivudine-resistant viral variants. Antimicrob Agents Chemother. 2002 May;46(5):1394-401. Last accessed on November 30, 2013.
6. Schinazi RF, Massud I, Rapp KL, et al. Selection and characterization of HIV-1 with a novel S68 deletion in reverse transcriptase. Antimicrob Agents Chemother. 2011 May;55(5):2054-60. Last accessed on November 30, 2013.
7. Herman BD and Sluis-Cremer N. Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors. In: Gallelli L, ed. Pharmacology. InTech, DOI: 10.5772/32969; 2012: p. 63-81. Last accessed on November 30, 2013.
8. Ma L, Hurwitz SJ, Shi J, et al. Pharmacokinetics of the antiviral agent beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine in rhesus monkeys. Antimicrob Agents Chemother. 1999 Feb;43(2):381-4. Last accessed on November 30, 2013.
9. Erickson-Viitanen S, Hou K, Lloyd R Jr, et al. Baseline Genotype/Phenotype, Virological Response, and Lack of de novo Resistance Mutation Generation During Therapy With Dexelvucitabine (Formerly Reverset) In Study RVT-203. Abstract presented at: 13th Conference on Retroviruses and Opportunistic Infections (CROI); February 5-8, 2006; Denver, CO. Abstract 632. Last accessed on November 30, 2013.
10. Cohen C, Katlama C, Murphy R, et al. Antiretroviral Activity and Tolerability of Reverset (D-d4FC), a New Fluoro-cytidine Nucleoside Analog, When Used in Combination Therapy in Treatment-Experienced Patients: Results of Phase IIb Study RVT-203. Abstract presented at: 3rd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Abstract WeOaLB0103. Last accessed on November 30, 2013.
Last Reviewed: November 30, 2013
Last Updated: November 30, 2013