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Novel NNRTI reduced viral loads in ART-naive men with HIV
UK-453,061 was well-tolerated and was associated with decreased viral loads at all dosing levels.
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UK-453,061, a short-term monotherapy agent, may offer potential as a future treatment option for patients with HIV.
In a recent study by German researchers, UK-453,061 (Pfizer) in twice-daily doses of 500 mg was associated with mean decreases of HIV RNA of 1.9 logs10 from baseline to seven days. A regimen of once-daily doses of 750 mg was associated with a mean decrease of HIV RNA of 2.0 logs10 after seven days.
UK-453,061, a non-nucleoside reverse transcriptase inhibitor (NNRTI) is active against NNRTI mutations, including K103N, Y181C/I and G190A/S.
Tim Jenkins PhD, an investigator from Pfizer Global Research and Development, presented trial results at the International AIDS Society Conference, held recently in Sydney.
Researchers from earlier studies of UK-453,061 concluded that two to three mutations are required to obtain resistant virus. The viruses resistant to UK-453,061 are still sensitive to efavirenz.
Monoclonal deep sequencing analyses of the most recent study are planned for presentation at The Interscience Conference on Antimicrobial Agents and Chemotherapy this month. The clinical program could eventually extend to children with HIV.
“The development of this compound is still very early, but I imagine once we understand that it is safe in long-term therapy, those things will be considered,” Jenkins said.
Early results promising
Forty-eight patients in the randomized, double blind, outpatient study had CD4 counts of greater than 250 cells/mm3 and viral loads greater than 5,000 copies/mL. All were men aged from 29 years to 41 years with HIV who had no prior exposure to an NNRTI and no NNRTI-resistant mutations. Patients either had no antiretroviral treatment experience or were off treatment for eight weeks or longer at the time of screening. All were diagnosed at least three months before enrollment.
Patients were given UK-453,061 or placebo for one week and were followed up at 40 days.
To evaluate twice-daily versus once-daily dosing regimens, 10 mg, 30 mg, 100 mg and 500 mg twice daily and 100 mg, 500 mg and 750 mg-once-daily doses were chosen. Six patients were randomly assigned to eight treatment arms including placebo. The study was done in two stages; the first stage was suspension doses and the second stage was tablets of various doses.
Viral load and UK-453,061 plasma concentration were measured in all participants.
Viral loads decrease
Doses of 200 mg or greater showed similar viral load reductions. All patients assigned 500 mg daily doses or greater achieved viral load reductions of at least 1.5 logs10.
In healthy volunteers, UK-453,061 was safe and well-tolerated in single does up to 1,800 mg and multiple dose studies up to 1,000 mg twice daily for 12 days.
For more information:
- Fätkenheuer G, Staszweski S, Plettenberg A, et al. Short-term monotherapy with UK-453,061, a novel NNRTI, reduces viral load in HIV infected patients. Presented at: The International AIDS Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney.