April 29, 2002
Posters at the Ninth Retrovirus Conference supply data in support of once-daily dosing for a new formulation of Zerit (d4T) (Abstract 411, 416), additional support of once-daily Fortovase/Norvir (Abstract 441), and new data on once-daily dosing of Kaletra (Abstract 409). There were also several studies using newer, not yet approved, antiretrovirals such as atazanavir (a protease inhibitor) and DPC 083 (an investigational non-nucleoside reverse transcriptase inhibitor) as part of a once-daily highly active antiretroviral therapy (HAART) regimen.
A large, Phase II, placebo controlled, prospective study of 783 people compared an extended-release formulation of Zerit (d4T XR) dosed at 100 mg once daily to the currently available formulation of immediate-release Zerit (Zerit IR) dosed at 40 mg twice daily (Abstract 411). The Zerit was used as part of a HAART regimen of Epivir (150 mg twice daily) and Sustiva (600 mg once daily). At the start of the study, it was determined that Zerit XR blood levels were just as high as those seen with Zerit IR (Abstract 416). A 24-week interim analysis of the planned 48-week study was reported at the Retrovirus Conference. Virologic and immunologic responses were nearly identical in the Zerit XR and IR groups. The safety, tolerability and efficacy profiles of Zerit XR also appear comparable to that of Zerit IR. This data will likely result in the approval of once-daily Zerit XR in the next year if the results are maintained at the 48 week analysis.
Once-daily regimens using the combination of Fortovase and Norvir (at 1600 mg and 100 mg) have been previously studied with promising results. However, the combination of Fortovase with Sustiva once daily is discouraged because of the induction of Fortovase metabolism. L. López-Cortéz studied the safety, efficacy and blood levels of Fortovase (1200 mg) with Sustiva (600 mg) with the addition of Norvir (100 mg) to see if a once-daily nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen, using these drugs, was feasible in people in whom NRTIs were withdrawn because of adverse events (Abstract 441). All people were NRTI and protease inhibitor experienced. All 22 people who entered the study with an undetectable VL remained undetectable, and 13 of the 20 people with a high viral load became undetectable. At 52 weeks, a total of 71 percent of the people had a viral load below 50 copies with a median CD4 cell count increase of 215 cells. Treatment had to be withdrawn in only one case, due to hepatitis. This regimen may be an effective once-daily alternative for people for whom NRTIs are no longer a good option.
One major concern about once-a-day dosing is that if a person skips a dose, they go a whole day without sufficient drugs in the blood to suppress HIV replication, whereas if they miss one dose of a twice-a-day regimen, they go only 12 hours before the next dose. Additional data is needed to determine if missing one dose of a once-daily HAART regimen will allow HIV replication and more frequent failure rates.