D-D4FC (Reverset) is a cytidine analogue reverse transcriptase inhibitor with potent antiviral activity in vitro (including activity against many viruses resistant to nucleoside/nucleotide reverse transcriptase inhibitors [NRTIs]), low mitochondrial toxicity and pharmacokinetic data supporting once-daily dosing.

In this presentation, Robert Murphy presented final data on the 10-day treatment study RVT-202, updating information, in particular, on the treatment-experienced patients initially cited at the XV International AIDS Conference in Bangkok, Thailand.¹

In this study, the primary endpoint was change from baseline HIV RNA. Ten treatment-experienced patients with HIV RNA greater than 1,000 were enrolled; 8 received active D-D4FC and 2 received a placebo.

All 10 patients had extensive prior therapy with NRTIs. Current treatment in those receiving active D-D4FC included: lamivudine (3TC, Epivir) being taken by 6 patients, 5 patients were on tenofovir (TDF, Viread), 3 on zidovudine (AZT, Retrovir), 1 on abacavir (ABC, Ziagen) and 1 on didanosine (ddI, Videx).

Five of the patients had the M184V mutation and 4 had at least 3 TAMs (2 with the 41, 210 pathway and 2 with the 67, 70 pathway). In 2 patients there were no NRTI mutations, and no study subject had K65R.

At the end of day 10, the mean change in viral load was 0.8 log (compared with 1.77 log in the treatment-naive population). Seven of the 8 D-D4FC patients had at least a 0.5 log decline, 4 achieved a viral load below 400 copies/mL and 1 achieved a viral load below 50 copies/mL.

Current treatment with lamivudine or tenofovir did not appear to blunt the response to treatment, and no particular genotypic pattern predicted response. For example, 1 of the 2 patients with the 41, 210 TAM pathway had a 0.7 log decline, while the other had a 0.2 response. No new toxicities were reported. Since D-D4FC can be metabolized to 5FC (an antifungal compound) and 5FU (a chemotherapy agent), a pharmacokinetic analysis at the end of the study found 5FC at a level less than 2% of that used for antifungal therapy, and no detectable 5FU.

The results of this study imply that D-D4FC will have activity against many viral strains with NRTI resistance. Not surprisingly, the viral load response is of a lower magnitude than that seen in treatment-naive subjects.

Clearly the short duration and small sample size of this study limit broad conclusions -- especially about genotypic predictors of response -- but these are promising enough results to warrant the 180-subject trial in treatment-experienced patients, which Murphy reported is currently half enrolled.

Footnote

1. Murphy RL, Schürmann D, Beard A, et al. Potent anti-HIV-1 activity of Reverset following 10 days of monotherapy in treatment-naive individuals. In: Program and abstracts of the XV International AIDS Conference; July 11-16, 2004; Bangkok, Thailand. Abstract MoOrB1056.