Efavirenz-related studies: genetics, smoking and TDM
Simon Collins, HIV i-Base
Several studies presented interesting results on the PK of efavirenz.
In an oral presentation reporting higher rates of antiretroviral switching by patients with pharmacogenetic markers (notably genotype changes in CYP2B6 G516T) associated with an increased risk of side effects, Colombo and colleagues from the Swiss HIV Cohort reported that patients were more likely to switch from efavirenz if they carried these alleles (42% vs. 27%). 
Bensemmane and colleagues from a multicentre French study reported on the routine use of therapeutic drug monitoring (TDM) to manage individual patients on efavirenz from 2002-2008. 
The target level, based on historical estimates was 1000-4000 ng/mL. Of the 2545 patients (33% women) prescribed efavirenz at 600mg once-daily, with at least one TDM result for Cmin, approximately 5% had levels below the limit of detection for the test (<10ng/mL) suggesting non-adherence. 12% patients had levels below the minimum target, 61% were in the target range and 22% had Cmin levels >4000 ng/mL.
Of the 549 patients with high levels, 41% (n=188) adjusted the efavirenz dose to one of four once-daily doses: 400mg, 300mg, 200mg or 100mg (groups 1 to 4, respectively).
Table 1. Median efavirenz levels in patients with Cmin >4000 ng/mL
|N||Baseline Cmin (ng/mL)||Cmin after adjustment (ng/mL)|
Although the poster abstract provided minimal details on the relationship between drug levels and toxicity, it reported that approximately that only 22% of patients making a dose adjustment continued to experience persistent side effects. As the study was unblinded patients who knew they had reduced their dose may have reported side effects differently.
A second poster by Fayet and colleagues from the Swiss Cohort Study reported results from a small prospective study using TDM to individualise efavirenz dosing in 15 patients on stable EFV-based HAART, with levels in the highest quartile. 
At baseline, median efavirenz Cmin was 8,409 ng/mL (IQR 6610-10,370). The five patients with levels between 75-95 percentile reduced the efavirenz dose to 400mg QD and then ten patients above the 95th percentile reduced to 200mg QD.
Following dose reductions, ten patients with results achieved the target of 25-75th percentile range (median 2,856, IQR 2192- 3157 ng/mL). Three months after the dose adjustment, all patients remained above the minimum 1000ng/mL lower target level and maintained viral load <40 copies/mL.
Cortes and colleagues presented results from a prospective 215 patients (13 women) in Chile, looking at both drug levels and genetics (CYP2B6: 516G>T and 983 T>C; and contitutive androstane receptor (CAR) rs2307424 polymorphisms). 
In the group as a whole, mean (+SD) levels were 3100 ng/mL (+1600), in samples taken a mean 11.9 hours (+1.6) post-dose. Eleven patients (5%) had levels <1000 and 45 (21%) had levels >4000ng/mL. Alleles at CAR, 516G>T and 983 T>C were present in 49%, 35% and 0% respectively, and were related to drug concentations in multivariate analysis (see Table 1).
As reported in other studies, c516 polymorphisms were related to efavirenz exposure.
This is the first report of the impact of the associations with the contitutive androstane receptor and the group also reported statistically significant lower levels in smokers compared to non-smokers (2.81 vs. 3.32 mg/L, p-0.02).
Table 2. Efavirenz drug exposure (mg/L) in relation to genetic plymorphisms
|CYP2B6 516||GG (n=90)||GT (n=87)||TT (n=30)||p|
|CAR rs2307424||CC (n=50)||CT (n=109)||TT (n=48)||p|
These posters show the potential for individualising dosing in patients who metabolise efavirenz more slowly (whether due to genetics, hepatitis coinfection etc) and who end up with levels higher than the upper limit of the recommended target range.
The association with smoking status has not previously been reported.
It is unclear if the study adjusted for weight differences and whether this would make a difference to the results. If there is an association with weight, then the association with smoking would be in the opposite direction (ie. smokers tend to weigh less, so levels may be higher rather than lower).
- Colombo S et al. Association of pharmacogenetic markers with premature discontinuation of first-line ART. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Oral poster O-03.
- Bensemmane R et al. Six years of routine therapeutic drug monitoring of efavirenz (EFV) in HIV-infected patients. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Poster abstract P-48.
- Fayet A et al. Successful TDM-guided efavirenz dose reduction in virologically-controlled patients. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Poster abstract P-47.
- Cortes C et al. Correlates of efavirenz exposure in HIV infected patients from Chile reveals novel associations iwith a polymorphism in the contitutive androstane receptor and smoking. 10th International Workshop on Clinical Pharmacology of HIV Therapy, 15-17 April 2009, Amsterdam. Poster abstract P-04.