NOTE: The development of dexelvucitabine for HIV treatment has been discontinued.
The study of dexelvucitabine as a nucleoside reverse transcriptase inhibitor (NRTI) HIV medicine was discontinued in 2006. The company developing the drug announced that this decision was based on safety concerns in a Phase IIb long-term extension study. In that study, dexelvucitabine was associated with a high incidence of severe hyperlipasemia. (Hyperlipasemia is a marker of pancreatic inflammation.)4
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
Half-life (T½): Following a single intravenous (IV) dose of dexelvucitabine in rhesus monkeys, the mean elimination half-life was measured at 3.6 hours.5 In a single-oral-dose study of dexelvucitabine (10 mg to 50 mg as buffered solution or 50 mg to 200 mg as enteric-coated tablets) in HIV-infected, treatment-naive male participants, the mean plasma half-life was approximately 12.3 hours.8
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.9
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 (TAMs). 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.10,11
Dosing in Clinical Trials
; Study 2034
: Study to evaluate the safety and effectiveness of three different doses of dexelvucitabine plus a background regimen and to compare dexelvucitabine to placebo
: HIV-infected, treatment-experienced participants; majority with TAMs present at screening
: Dexelvucitabine 50, 100, or 200 mg administered once daily versus placebo, each in combination with an antiretroviral (ARV) regimen previously taken by the participant, for the initial 2 weeks of the study (add-on phase), followed by a 14-week optimized treatment phase. During the final 8-week safety phase, placebo participants were allowed to cross over to treatment with dexelvucitabine.10,11
(See references cited above for information on study results.)
: Study 9014
: Long-term extension of Study 203 to evaluate two doses of dexelvucitabine plus a background regimen
: HIV-infected, treatment-experienced
: Dexelvucitabine 100 and 200 mg, with or without lamivudine or emtricitabine. (As results from Study 203 became available and demonstrated the increased efficacy of dexelvucitabine without lamivudine or emtricitabine, some Study 901 participants who had been previously on lamivudine or emtricitabine were transitioned to regimens without lamivudine or emtricitabine).4
(See references cited above for information on study results.)
Based on safety concerns arising in Study 901, the company studying dexelvucitabine terminated Study 204. Study 204 was a Phase IIb trial to compare the safety and effectiveness of dexelvucitabine 200 mg to that of lamivudine 300 mg, each in combination with an optimized background regimen in HIV-infected, treatment-experienced adults who have failed and/or harbor HIV resistant to three classes of ARV therapies.4,12
In 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 in 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. Other serious adverse events possibly related to dexelvucitabine treatment included anemia, neutropenia, hypertriglyceridemia, and pancytopenia.11
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
Dexelvucitabine should not be co-administered with didanosine because of a risk of elevated lipase and pancreatitis.11
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/134379-77-4. Last accessed on November 19, 2014.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on November 19, 2014.
- Incyte Corporation: Press Release, dated September 8, 2003. Incyte and Pharmasset Enter into a Collaborative Licensing Agreement for a Phase II HIV Drug. Available at: http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=446461&highlight=. Last accessed on November 19, 2014.
- 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. Available at: http://investor.incyte.com/phoenix.zhtml?c=69764&p=irol-newsArticle&ID=837677&highlight=. Last accessed on November 19, 2014.
- 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC127174/. Last accessed on November 19, 2014.
- 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088218/. Last accessed on November 19, 2014.
- 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. http://www.intechopen.com/books/pharmacology/molecular-pharmacology-of-nucleoside-and-nucleotide-hiv-1-reverse-transcriptase-inhibitors. Last accessed on November 19, 2014.
- Murphy RL, Schürmann D, Kravec I, et al. Pharmacokinetics, Safety and Antiviral Activity of the Nucleoside Reverset Following Single Doses in HIV-1 Infected Patients. Abstract presented at: 2nd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment; July 13-16, 2003; Paris, France. Abstract 545. Available at: http://www.iasociety.org/Default.aspx?pageId=12&abstractId=10069. Last accessed on November 19, 2014.
- 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC89084/. Last accessed on November 19, 2014.
- 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. 13th Conference on Retroviruses and Opportunistic Infections (CROI); February 5-8, 2006; Denver, CO. Levin: Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2006. Available at: http://www.natap.org/2006/CROI/CROI_38.htm. Last accessed on November 19, 2014.
- 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. 3rd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment; July 24-27, 2005; Rio de Janeiro, Brazil. Levin: Reverset (d4FC), new NRTI: phase IIb data; Conference reports for National AIDS Treatment Advocacy Project (NATAP); 2005. Available at: http://www.natap.org/2005/ias/ias_2.htm. Last accessed on November 19, 2014.
- Incyte Corporation. A Randomized, Double-Blind, Phase II Study Comparing the Anti-Retroviral Safety and Efficacy of Dexelvucitabine (DFC) 200 mg Once Daily to Lamivudine (3TC) 300 mg Once Daily in Addition to Optimized Background Therapy in HIV-1 Infected Subjects Who Have Failed and/or Harbor HIV With Resistance Mutations to NRTIs, PIs, and NNRTIs. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 7, 2006. NLM Identifier: NCT00300573. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00300573. Last accessed on November 19, 2014.
Last Reviewed: November 19, 2014