Abacavir looks likely to be the latest anti-HIV drug to become available for once-daily dosing after a study, presented as a late-breaker to the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago on September 16th, found that a single 600mg dose of the drug a day was safe and effective in combination with 3TC and efavirenz.
Professor Brian Gazzard of Chelsea and Westminster Hospital, London, the UK’s leading HIV treatment centre, presented data from the GlaxoSmithKline (GSK) sponsored ZODIAC study (CNA30021).
The ZODIAC study was a 48 week randomised, multicentre, placebo-controlled trial involving patients naïve to anti-HIV drugs. Its aim was to compare the safety and efficacy of a once daily 600mg dose of abacavir taken in combination with once daily doses of 3TC and efavirenz against a 300mg of abacavir twice- daily, again in combination with once daily 3TC and efavirenz.
A total of 770 individuals received study medication. Median HIV viral load at baseline was 4.8910log c/mL and median CD4 cell count was 262 cells/mm3.A substantial proportion of study participants had high viral loads, with 44% of individuals having an HIV viral load above 100,000 copies/mL.
By week 48, 66% of patients who received once-daily abacavir had an HIV viral load below 50 copies/mL compared to 68% of those given the drug twice daily. Virological failure was also comparable between the two arms, with 10% of individuals given abacavir once daily experiencing virological rebound compared to 8% of the twice daily arm. The difference between the two arms was not statistically significant.
The median gain in CD4 cell count by week 48 was also comparable, with individuals taking once daily abacavir experiencing an increase of 188 cells/mm3 from baseline compared to an increase of 200 cells/mm3 from baseline for patients in the twice daily arm.
There were no new safety concerns about once daily abacavir dosing, and comparable numbers of patients in both arms of the study experienced a hypersensitivity reaction to abacavir (9% once daily versus 7% twice daily). For both arms of the trial this level of hypersensitivity is significantly higher than the 3% incidence suggested by earlier studies.
Abacavir once daily in combination with 3TC and efavirenz is an effective HAART regimen, which is as good as twice daily abacavir with once-daily 3TC and efavirenz and as such, the investigators concluded, it provides an “important new treatment simplification option.”
GlaxoSmithKline is developing a once daily tablet containing abacavir and 3TC, partly in response to the threat posed by Gilead's plans to develop a once daily tablet containing tenofovir and FTC (emtricitabine). In its communications this week, the company has been keen to stress that once the new tablet is approved, a once daily regimen of two tablets will be possible for patients taking abacavir, 3TC and efavirenz. The company clearly hopes that the results of CNA30024 (presented on Sunday) will convince doctors and patients that abacavir/3TC/efavirenz is just as good as the current gold standard in first-line therapy, AZT/3TC/efavirenz, and that the new tablet will quickly be adopted as the standard of care in the US and Europe when it is launched some time next year.
A pharmacokinetic study also presented today showed that abacavir has a much longer intracellular half-life than previously reported. All nucleoside analogues must undergo phosphorylation into a triphosphate form before they become active against HIV within cells, and so pharmacokinetic studies of nucleoside analogues must measure intracellular levels rather than plasma levels. The mean intracellular half-life of carbovir triphosphate (the phosphorylated form of abacavir) is 20.6 hours, according to GlaxoSmith Kline researchers.
The half-life was calculated by taking a normal abacavir dose (300mg) in the morning, witholding the evening dose and measuring carbovir triphosphate levels in peripheral blood mononuclear cells over the following 24 hours in 20 volunteers on a stable abacavir-containing regimen.
Gazzard BG et al. Abacavir once-daily plus lamivudine once-daily with efavirenz once-daily is well-tolerated and effective in the treatment of antiretroviral therapp naïve adults with HIV-1 infection (ZODIAC Study: CNA30021). 43rd ICAAC, abstract H-1722b, Chicago, September 14 – 17th, 2003.
Piliero P et al. A study examining the pharmacokinetics of abacavir and the intracellular carbovir triphosphate (GSK protocol CNA10905). 43rd ICAAC, abstract A-1797, Chicago, September 14-17, 2003.