Browsing by Author "Gordon, David N"

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    Abacavir Once or Twice Daily Combined With Once-Daily Lamivudine and Efavirenz for the Treatment of Antiretroviral-Naive HIV-Infected Adults: Results of the Ziagen Once Daily in Antiretroviral Combination Study
    (2005-04-01) Moyle, Graeme J; DeJesus, Edwin; Cahn, Pedro; Castillo, Steve A; Zhao, Henry; Gordon, David N; Craig, Charles; Scott, Trevor R
    The long intracellular half-life of abacavir (ABC) supports its once-daily use, and this would be expected to simplify treatment if ABC could be given as part of a complete once-daily regimen. A randomized double-blind clinical trial compared the efficacy and safety of 600 mg of ABC administered once daily (n = 384) versus 300 mg of ABC administered twice daily (n = 386) in combination with 300 mg of lamivudine (3TC) and 600 mg of efavirenz (EFV) administered once daily in antiretroviral-naive patients over 48 weeks. The baseline median plasma HIV-1 RNA level was 4.89 log10 copies/mL (44% with viral load >100,000 copies/mL), and the median CD4+ cell count was 262 cells/mm3. ABC administered once daily was non-inferior to the twice-daily regimen, with 66% and 68% of patients in these respective treatment arms achieving a confirmed plasma HIV-1 RNA level <50 copies/mL (95% confidence interval: −8.4%, 4.9%). The ABC once-daily and twice-daily regimens were similar with respect to infrequency of virologic failure (10% vs. 8%), emergence of resistance mutations, CD4+ cell increases from baseline (median, 188 vs. 200 cells/mm3), safety profile, and incidence of ABC-related hypersensitivity reactions (9% vs. 7%). ABC administered once daily in combination with 3TC and EFV administered once daily was non-inferior to the ABC twice-daily dosing schedule when combined with 3TC and EFV over 48 weeks. Current clinical management of HIV-1 disease necessitates use of a multidrug regimen generally including 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a third agent.1 Good adherence to potent antiretroviral therapy is critical in achieving a successful outcome. High pill burdens, dosing frequencies, risk of adverse events (AEs), drug interactions, and inconvenient dietary restrictions all potentially affect adherence and, ultimately, treatment efficacy.2,3 Patient preference surveys suggest that persons with HIV may prefer compact once-daily regimens if the efficacy and tolerability of these regimens are similar to those of the twice-daily standard of care regimens.3 Some antiretroviral drugs that have half-lives suitable for administration once a day (OAD) cannot be used together because of drug interactions and dietary restrictions. An expansion in the number of antiretroviral drugs approved for OAD dosing increases the potential for OAD therapy to become the preferred initial therapy. The NRTI abacavir (ABC) has demonstrated durable efficacy as a component of numerous regimens administered at a dose of 300 mg twice daily.4-6 A multidrug combination of 300 mg of ABC administered twice daily with lamivudine (3TC) and efavirenz (EFV) has been compared with 300 mg of zidovudine (ZDV) administered twice daily with 3TC and EFV and has resulted in similarly potent and durable virologic suppression (<50 copies/mL), superior CD4+ cell recovery, and good tolerability, including an improved hematologic profile over 48 weeks.7 Recent pharmacokinetic studies in HIV-1-infected adults have shown that the active drug moiety of ABC, carbovir triphosphate (CBV-TP), has a long intracellular half-life (>20 hours) that would support OAD dosing of 600 mg of ABC.8-10 A small clinical study in which 600 mg of ABC administered OAD was compared with 300 mg of ABC 300 administered twice daily suggested that ABC could be administered OAD and supported further investigation of this dosing schedule.11 The Ziagen Once Daily in Antiretroviral Combination (ZODIAC) therapy study was a noninferiority clinical trial conducted over 48 weeks that compared the efficacy and safety of triple drug therapy with 600 mg of ABC administered OAD versus 300 mg of ABC administered twice daily, combined with OAD 3TC and EFV, in the treatment of antiretroviral-naive adults.