Elvucitabine Monotherapy Demonstrates Antiviral Activity in 7-day Study

Elvucitabine (L-Fd4C) is an L-cytosine nucleoside analog with a long half-life in the body. A previous small study showed that various doses of elvucitabine plus lopinavir/ritonavir (Kaletra) suppressed HIV viral load by as much 2 log copies/mL over 21 days. While the earlier trial demonstrated the short-term safety of elvucitabine, it was not able to determine how much of the antiviral effect was attributable to the new agent versus lopinavir/ritonavir.

As reported at the recent ICAAC, researchers carried out a subsequent study of elvucitabine monotherapy. The study included 24 HIV positive participants, of whom all but one were men. The mean baseline HIV RNA level was about 4.75 log copies/mL. Subjects had minimal previous antiretroviral treatment experience, and genotypic testing showed they did not have mutations associated with resistance to elvucitabine or lopinavir/ritonavir.

Participants were randomly assigned to receive 10 mg once-daily elvucitabine or placebo for 7 days. Then, subjects treated with elvucitabine were given lopinavir/ritonavir for 21 days to decrease the likelihood of elvucitabine resistance.

Results

By Day 7, HIV viral load decreased by a mean 0.85 log copies/mL in the elvucitabine arm, compared with essentially no change in the placebo arm (P < 0.001).

In the elvucitabine arm, HIV RNA continued to decrease in a concentration-dependent manner after Day 7.

Subjects in the elvucitabine arm experienced a mean CD4 increase of 62 cells/mm3 by Day 7, compared with 9 cells/mm3 in the placebo arm.

The half-life of elvucitabine in plasma and peripheral blood mononuclear cells (PBMCs) was approximately 100 hours.

Plasma and PBMC elvucitabine concentrations were detectable up to 14 days after the last dose.

Elvucitabine concentrations remained above the IC50 (level required to reduce viral replication by 50%) until Day 21, or up to 14 days after the last dose.

Elvucitabine remained detectable in PBMCs at the final measurement.

On Day 21, the maximum decrease in viral load from baseline was 1.73 log copies/mL.

No elvucitabine-associated safety issues or emergence of resistance was observed.

Conclusion

"These results confirm that elvucitabine monotherapy demonstrates significant antiviral activity over 7 days," the researchers concluded. "Elvucitabine's long plasma and intracellular [half-life] and concentration-dependent efficacy may provide a better barrier to resistance than antiviral agents with short half-lives."

They added that, "This study serves as a basis for future clinical trials with innovative dosing schemes of elvucitabine in combination with other antiretroviral agents." The drug's long half-life suggests dosing less than once daily may be possible.

MDSPS and Universite de Montreal, Montreal, Canada; Achillion Pharmaceuticals, Inc., New Haven, CT; Charite U Med, Berlin, Germany.

10/10/06

Reference
P Colucci, J Pottage, H Robison, and others. Efficacy and novel pharmacology of elvucitabine in a 7 day placebo controlled monotherapy study. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract H-1670d.

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