Background:  Current antiretroviral drugs differ in their relative plasma elimination half-lives. The reported t_1/2 of EFV is 40 to 55 hours; therefore EFV concentrations may persist at therapeutic levels for longer than 1 week following discontinuation. If drugs with a shorter half-life are stopped at the same time as EFV, patients will effectively be receiving monotherapy for a significant period. This may be important if there is ongoing viral replication, as nNRTI-resistant variants may be selected.

Methods:  For 8 HIV-1⁺ patients who took part in an extended pharmacokinetics study, blood was drawn at baseline (day 0) and at days 4, 7, 14, and 21 after stopping EFV. Plasma samples were analyzed for EFV concentrations by HPLC and the half-life determined by regression analysis. Viral RNA⁺- resistance testing was performed at each time point. A further 25 patients who stopped EFV after short-course antiretroviral therapy following seroconversion were assessed to obtain virological data on patients stopping EFV 5 to 7 days prior to other agents in the regimen. These patients had resistance testing before commencement of treatment and an average of 4 weeks after stopping EFV.

Results:  In the pharmacokinetics study the reasons for stopping EFV were virologic failure (n = 4), toxicity (n = 1), stopping 1 of 2 NNRTI (n = 2), and post seroconversion (n = 1). The median EFV concentration at day 0 (n = 8) was 3004 ng/mL (range 894 to 8216); at day 7 was 310 ng/mL (<40 to 4478); at day 14 was 149 ng/mL (<40 to 1845), and at day 21 was 62 ng/mL (<40 to 637). The calculated half-life ranged from 36 to 100 hours. Of the 25 patients in the virologic study only 1 exhibited resistance 4 weeks after stopping treatment. However this was also present prior to EFV therapy. Using a protein-corrected EC₉₅ value of 93 ng/mL for wild type virus, 4/7 patients had EFV concentrations above this at day 7, 3/7 at day 14, and 2/7 at day 21.

Conclusions:  Based on virologic data it would appear reasonable to stop EFV 7 days prior to stopping other shorter-acting drugs in the regimen. It may also be possible to consider exchanging EFV for a drug with a shorter half-life before stopping all drugs. However, based on this extended pharmacokinetics data, it may be more prudent to increase the stop window to 2 weeks to minimize the potential for selecting for nNRTI resistance. These findings will have implications for conserving future therapeutic options and also stopping other agents with long plasma or intracellular half-lives.

Keywords: PHARMACOKINETICS; EFAVIRENZ; STOP STUDY