DFC is a nucleoside reverse transcriptase inhibitor (NRTI) which was under development by Pharmasset Pharmaceuticals and Incyte. Its generic name is elvucitabine and its trade name was to be Reverset. DFC was formerly known as DPC-817 whilst under development by Du Pont and then Bristol-Myers Squibb. It is also known as D-d4FC.

DFC is a cytidine analogue that is active against viruses resistant to AZT (zidovudine, Retrovir) and 3TC (lamivudine, Epivir). It is also active against viruses with thymidine analogue mutations (TAMs) such as the 215 mutation, but not against the multinucleoside resistance mutations Q151M or 69SS. The drug is closely related in structure to racivir, another NRTI being developed by Pharmasset.

Development of DFC was stopped in April 2006 following dangerous elevations of the enzyme lipase in the blood in patients taking 200mg DFC without 3TC or FTC (emtricitabine, Emtriva) in study 901.

Effectiveness

DFC has a long half-life and a favourable side-effect profile, with no known mitochondrial toxicity or raised lactate levels. Studies demonstrated that once-daily DFC is well tolerated and effective in treatment-naive patients, and those with resistance mutations for other NRTIs.

One dose-ranging study study compared buffered and enteric-coated formulations of DFC in 18 HIV-infected men, and found that the enteric-coated formulation did not produce 5FC, a breakdown product that may cause toxicity. After 48 hours, the mean viral load reduction from a single dose of D-D4FC was 0.37 log₁₀ with the lowest dose of 10mg. One subject with resistance mutations indicating prior exposure to AZT and non-nucleoside reverse transcriptase inhibitors (NNRTIs) experienced a viral load drop of 0.61 log₁₀ (Murphy 2003; Stuyver 2004).

In a second study, 30 treatment-naive patients were randomised to receive placebo, or 50, 100 or 200mg DFC once daily for ten days. All three treatment groups showed a large decrease in viral loads during treatment, with the patients receiving 200mg showing a mean decrease in viral load of 1.77 log₁₀ by day 10. Genotype analysis failed to find any new mutations in the virus isolated from these patients and pharmacokinetic analysis confirmed that the maximal plasma concentration of DFC in the patients receiving 200mg was higher than the levels required to inhibit the activity of HIV with mutations associated with AZT, d4T (stavudine, Zerit), 3TC or tenofovir (Viread) treatment. Similarly, in treatment-experienced patients failing their current antiretroviral drug regimen, adding once-daily 200mg DFC to their current regimen for ten days led to a mean fall in viral load of 0.8 log₁₀ (Murphy 2004).

A phase IIb trial of DFC in the United States, Germany and France has shown that the drug is active in treatment-experienced patients. The 199 patients were first randomised to add one of three doses of DFC or placebo to their failing drug regimen for two weeks. This caused a 0.7 log₁₀ drop in viral load in the 200mg group, significantly greater than the placebo, 50mg and 100mg groups. The drugs effects were unaffected by co-administration with tenofovir (Viread), AZT or abacavir (Ziagen). However, its activity was lower if combined with the similar drugs 3TC or FTC (emtricitabine, Emtriva). It was the extension of this trial in patients who were not taking 3TC or FTC that led to the observation of increased lipase levels and the discontinuation of the drug.

Resistance

A test-tube study has found that the following mutations in the reverse transcriptase gene cause resistance to DFC: I63L, K65R, K70N, K70E and R172K (Hammond 2005).

References

Cohen C et al. Antiretroviral activity and tolerability of Reverset (D-d4FC), a new fluorocytidine nucleoside analog, when used in combination therapy in treatment-experienced patients: results of phase IIb study RVT-203. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract WeOaLB0103, 2005.

Hammond JL et al. In vitro selection and analysis of human immunodeficiency virus type 1 resistant to derivatives of beta-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine. Antimicrob Agents Chemother 49: 3930-3932, 2005.

Murphy RL et al. Pharmacokinetics, safety and antiviral activity of the nucleoside reverset following single doses in HIV-1 infected patients. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris, abstract 545, 2003.

Murphy RL et al. Potent anti-HIV-1 activity of Reverset^TM following 10 days of monotherapy in treatment-naﶥ individuals. Fifteenth International AIDS Conference, Bangkok, abstract MoOrB1056, 2004.

Stoddart C et al. Activity of the cytidine analog Reverset (RVT) against 3TC-resistant HIV-1 in SCID-hu Thy/Liv mice. HIV DART, Naples, Florida, 2002.

Stuyver LJ et al. Potent antiviral effect of reverset in HIV-1-infected adults following a single oral dose. Antivir Ther 9: 529-536, 2004.