Novel NRTI elvucitabine active against HIV in a 7-day monotherapy study

The investigational nucleoside reverse transcriptase inhibitor elvucitabine demonstrated potent and prolonged anti-HIV activity in a seven-day monotherapy study, according to late-breaking data presented on Friday at the Forty-Sixth Interscience Conference on Antiretroviral Agents and Chemotherapy (ICAAC) in San Francisco.

Elvucitabine (also known as L-Fd4C) is an L-cytosine nucleoside analogue being developed by Achillion Pharmaceuticals of New Haven, Connecticut, in the U.S. A small study reported at last year’s ICAAC showed that various doses of elvucitabine plus lopinavir/ritonavir (Kaletra) suppressed HIV RNA by as much 2 log₁₀ copies/mL over 21 days.

The previous trial demonstrated the short-term safety of elvucitabine, but was not able to determine how much of the observed antiviral effect was attributable to the new drug and how much to lopinavir/ritonavir. Accordingly, researchers then carried out a study of elvucitabine used as monotherapy.

The present Phase II double-blind study, described by Philippe Colucci of the University of Montreal, included 24 HIV-positive participants who were randomly assigned to receive 10mg once-daily elvucitabine or placebo. After seven days on elvucitabine monotherapy, these patients were give lopinavir/ritonavir for an additional 21 days in order to reduce the risk of drug resistance, since elvucitabine remains in the body for a prolonged period.

All participants but one were men, and all but one were white; the average age was about 40 years. The presenter noted that future multicentre trials will aim to enrol a more diverse study population.

Baseline characteristics were generally similar in both arms, but participants randomised to the elvucitabine group had a slightly lower CD4 cell count than those in the placebo arm (mean 320 vs 403 cells/mm³). The mean HIV RNA level was about 4.75 log₁₀ copies/mL. Patients had minimal previous antiretroviral treatment experience, and genotypic testing showed that they did not have mutations associated with resistance to elvucitabine or lopinavir/ritonavir (M184V, M184I, D237E).

By Day 7, HIV viral load declined by an average of 0.85 log₁₀ copies/mL from baseline in patients taking elvucitabine, compared with essentially no change in the placebo group (p 3, respectively. HIV RNA continued to decrease even after stopping the drug, but the decline became less pronounced as elvucitabine concentrations dropped. On Day 21 (14 days after the last elvucitabine dose), the maximal viral load decrease was 1.73 log₁₀ copies/mL, before rising again.

Pharmacokinetic analyses showed that the overall half-life of elvucitabine was about 100 hours, and there were still detectable concentrations in plasma and peripheral blood mononuclear cells at Day 21. Maximum concentrations and maximum trough levels of plasma elvucitabine were attained on the final day of dosing, but concentrations remained above the IC₅₀ (the level at which viral replication is reduced by 50%) for up to 14 days after discontinuation.

Overall, elvucitabine was well-tolerated. No major safety issues were identified, and the emergence of virus with resistance to elvucitabine or lopinavir/ritonavir was not observed.

The researchers concluded that, “These results confirm that elvucitabine monotherapy demonstrates significant antiviral activity over seven days of dosing.” They added that the drug’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.”

Based on the results of this and previous studies, Achillion plans to proceed with larger clinical trials of elvucitabine in combination with other antiretroviral agents. If the drug proves safe and effective over longer periods in more patients, it offers the prospect of an antiviral medication that may be able to be administered less often than once daily.