October 30, 2001
Some physicians and patients believe that one important way therapy will be made easier is by reducing dosing frequency to once daily. Data from other areas of medicine indicate that once-daily regimens are somewhat better adhered to by patients than twice-daily regimens (although statistically significant differences have not been demonstrated) and that dose timing accuracy may improve. One key to this is providing once-daily regimens with optimal potency, low tablet volume and preferably with a second future once-daily option. Those who argue against the once-daily approach say that if a dose is missed then therapy is missed for a full 24-hour period, creating a greater risk of viral escape. Additionally, some patients may prefer to take one pill twice a day rather than, say, five pills once a day. Unfortunately, the available triple nucleoside combined pill for one tablet twice daily dosing, Trizivir, is not suitable for everyone, as its efficacy appears diminished in higher viral loads and some individuals have intolerance to the AZT or abacavir components.
The range of once-daily options is expanding rapidly with the potential for a sequence of once-daily therapy to be available in the next 12-18 months. Already approved for once-daily use are ddI and EFV. Additional nucleosides for once-daily use include 3TC, FTC, DAPD and possibly abacavir, as well as an extended-release formulation of d4T. Nevirapine is being evaluated for once-daily use in the NNRTI class and a once-daily dosing regimen of saquinavir 1,600mg with ritonavir 100mg has demonstrated good efficacy in first protease inhibitor patients. A low tablet volume (two pills) once-daily protease inhibitor called atazanavir is also in development and appears at least as active as nelfinavir. A long list, but what about efficacy and durability?
A French study of a cohort of 40 antiretroviral-naive patients initiated on a once-daily regimen of ddI, EFV and FTC reported durable efficacy of this regimen over a remarkable two years of follow-up. Patients entering the cohort had a baseline viral load of 4.77 log and CD4 of 396 cells/mm3. At two years of follow-up, 33 of the original 40 patients remained in the study, with only three discontinuations due to adverse events (two related to CNS effects with efavirenz, one due to gastrointestinal upset) and one due to viral rebound. A further three left for personal reasons (including one accidental death).
By intent-to-treat (ITT) analysis, 33/40 (82.5%) patients maintained <400 copies/ml. The ITT success in the nine patients who commenced with a viral load above 100,000 copies/ml was 89%. This performance is similar to or better than large studies of standard of care regimens. However, one must interpret cohort data with some caution as patients in these small studies are often a select and very well supported bunch who tend to do better than larger study populations.
The data certainly provide support for researchers forging ahead with once-daily therapy studies.
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