Drug levels can persist for more than two weeks after stopping efavirenz
Simon Collins, HIV i-Base
How to stop treatment safely is arguably as important a management issue as how to correctly initiate treatment, but it has been the focus of far less research. As antiretroviral drugs have different plasma and intracellular half-lives, a strategy to safely discontinue treatment may be essential in order to avoid resistance.
Indeed, several treatment interruption studies have reported cumulative risk for developing NNRTI resistance with each interruption when using efavirenz (EFV, Sustiva, Stocrin) based regimens, when all drugs have been stopped at the same time. Other regimen-switching or cycling studies have shown greater virological benefits when efavirenz is included, and residual antiviral activity may be a plausible explanation for the improved results in those arms.
Steve Taylor from Birmingham Heartlands Hospital presented results from patients who were either stopping or switching efavirenz due to treatment failure or toxicity, or after a planned short course of treatment. Drug elimination takes five times the half-life of a compound and as the plasma half-life of efavirenz is estimated at 40-55 hours this theoretically risks monotherapy with a drug with a low genetic resistance barrier for a significant time.
Ten patients (six Caucasian men, four African women) were followed in an intensive PK study with EFV plasma levels measured at days 0, 4, 7, 14 and 21 by HPLC. A second group of 25 patients who were stopping a short course of antiretroviral therapy initiated following seroconversion, stopped efavirenz five to seven days prior to the other drugs in their regimen. Resistance testing was used at different times for each group.
In this small group, the calculated half-life in the eight patients in the PK study actually ranged from 32-100 hours. Values >1000ng/mL were considered therapeutic and those between 100 to 1000ng/mL sub therapeutic but sufficient to produce selective pressure on replicating virus. Efavirenz concentrations after discontinuation are shown below:
Table 1: Efavirenz concentrations after discontinuation
|Median (ng/mL)||Range (ng/mL)|
|Baseline||3004||894 – 8216|
|Day 7||310||894 – 8216|
|Day 14||149||<40 – 1845|
|Day 21||62||<40 – 637|
Individual cases included in the oral presentation at the conference showed this extreme variability between patients. A 64-year-old Caucasian man retained levels of efavirenz >100ng/mL three weeks after stopping efavirenz (he continued to take Combivir plus tenofovir) and showed a plasma half-life close to 150 hours. The other four Caucasian men had expected half-lives of 40-50 hours.
The four African women in the study had considerably longer half-lives than the expected mean ranging from 116 –115 hours. Two of these women were found to have extremely high baseline concentrations close to 10,000 ng/mL at baseline and three of the four women maintained ‘therapeutic’ levels of efavirenz (>1000ng/mL) two to three weeks after stopping treatment.
The 25 patients stopping treatment in the virologic study (23 Caucasian men, one Black man, one Black woman) continued Combivir for one week after discontinuation of efavirenz. No new resistance was detected between baseline and week 4 in this group.
The study concluded with a reference to the BHIVA (British HIV Association) guidelines, which recommend, when stopping an NNRTI, to either continue nucleoside for a further week, or to switch the NNRTI to a PI and use three drugs with similar (short) half-lives when stopping all drugs at the same time. A suggestion from the audience was that ritonavir could be used to speed up elimination, but this was unsupported by research.
On the basis of these data, even further caution may be necessary in many individuals, and the results from ACTG 5095 below suggest this is true for African-American women in particular, if efavirenz is to be stopped without risk of developing resistance.
Taylor S, Allen S, Fidler S et al. Stop study: after discontinuation of efavirenz, plasma concentrations may persist for two weeks or longer. 11th CROI 2004, Abstract 131.