Once daily Reverset safe and effective over ten days in treatment-naïve and –experienced patients

The novel nucleoside analogue D-D4FC (Reverset) is well tolerated and effective in both treatment-naïve and –experienced HIV-positive patients, and can be dosed once daily, according to a pair of placebo-controlled trials presented on Monday at the Fifteenth International AIDS Conference in Bangkok.

D-D4FC is a cytidine analogue under development by Incyte and Pharmaset, which is known from test tube studies to be effective against HIV resistant to AZT, 3TC and other nucleoside analogues. Since the drug has a long half-life in vivo, and is known to have a favourable side-effect profile, with no known mitochondrial toxicity or raised lactate levels, these studies was designed to assess the safety, tolerability and efficacy of once-daily dosing in treatment-naïve patients, and in those failing their current antiretroviral regimen.

Thirty treatment-naïve HIV-positive patients were recruited for the ten-day dose-escalation study. All of the patients had more than 50 CD4 T-cells/mm³ and viral loads above 5000 copies/ml.

The patients received placebo, or 50, 100 or 200mg D-D4FC once daily for ten days, during which time all three treatment groups showed a large decrease in viral loads. By day 10, the patients receiving the highest dose of 200mg D-D4FC showed a mean decrease in viral load of 1.77 log₁₀ copies/ml, with 88% of this group having fewer than 400 copies/ml. Following withdrawal of the drug, viral loads in the treatment groups slowly returned to baseline.

Genotype analysis failed to find any new mutations in the virus isolated from these patients. Furthermore, pharmacokinetic (PK) analysis confirmed that the maximal plasma concentration (C_max) of D-D4FC in the patients receiving 200mg (mean 9.8 µM) was higher than the levels that inhibit the activity of HIV with thymidine analogue mutations associated with AZT or d4T treatment or the mutations M184V or K65R (associated with 3TC and tenofovir treatment respectively) in test tube studies. This suggests that 200 mg D-D4FC once daily is likely to be effective in patients with virus resistant to 3TC and tenofovir.

Following these promising findings, the investigators went on to initiate a small placebo-controlled trial of D-D4FC in HIV-infected patients who were failing their current antiretroviral drug regimen (viral loads above 1000 copies/ml), including 3TC or tenofovir. After adding once-daily 200mg D-D4FC to their current regimen, ten days of therapy with the drug led to a mean fall in viral load of 0.8 log₁₀ copies/ml, with four of the eight patients having fewer than 400 copies/ml, and one fewer than 50 copies/ml. In contrast, the two patients receiving placebo showed no change in viral load over the same time period. None of these patients developed any resistance mutations over the ten-day treatment with D-D4FC or placebo.

In both trials, no patients experienced serious adverse events over the ten days of treatment. Dr. Robert Murphy, presenting, concluded by mentioning that a phase IIb trial of D-D4FC in treatment-experienced patients is currently recruiting participants in the United States, Germany and France. If the preliminary findings presented at the conference are to be replicated in this trial, they bode well for the future of this drug, which may become a useful option for patients infected with virus resistant to other nucleoside analogues.