Race affects absorption and clearance of efavirenz
3 April 2004. Related: Conference reports, PK and drug interactions, Side effects, CROI 11 (Retrovirus) 2004.
Simon Collins, HIV i-Base
Heather Ribaudo followed the UK efavirenz study with particularly supportive results from a sub-study from ACTG 5095 that randomised patients in a double-blind placebo controlled trial to either efavirenz (EFV, Sustiva, Stocrin) + Trizivir (AZT+3TC+abacavir) or to Trizivir alone.
This sub-study looked at efavirenz-related toxicity over the first 24 weeks of treatment. Plasma levels of efavirenz at 1, 4, 12 and 24 weeks obtained from 190 patients (36 women and 154 men) were analysed in relation to toxicity and virological response. 
Race distribution was 53% white, 32% Black and 15% Hispanic. Median weight was 75kg (range 46-186kg).
White non-Hispanic patients had a 32% increase (95 CI, 15 – 51%; p <0.001) in clearance compared to Black and Hispanic subjects. Both clearance and volume of distribution were associated with weight (p<0.001). There was no apparent association with gender (p >0.26) or HCV coinfection.
There was some evidence of an increasing rate of EFV discontinuation with decreasing clearance (p=0.052) and increasing Cmax (p=0.048). Sixteen percent of patients discontinued efavirenz during the first 24 weeks (n=31) due to CNS symptoms (n=5), rash (n=5), other toxicity (n=4), subject/clinician decision (n=6), and non-compliance (n=6). There was no apparent association between EFV pharmacokinetics and rates of first CNS toxicity or viral load of <200 copies/mL (for clearance, p=0.99, p=0.46, respectively).
In a second presentation from the same ACTG sub-study Haas and colleagues looked for a genetic basis of efavirenz clearance by identifying single nucleoside polymorphisms in CYP2B6, 3A4, 3A5 and MDR1 enzymes using real-time PCR. 
The functional G to T change at position 516 that identifies CYP2B6 *6 and *7 haplotypes was found in 20% of Black patients compared to only 3% of white patients, and was associated in higher efavirenz concentrations and lower clearance in all populations.
|Number of patients||78||60||14|
|Median AUC24 µg.h/L||44||60||130|
The CYP3A4 1B (A392G) G/- genotypes were also associated with higher EFV levels (p <0.001) although A/A genotype was rare among non-whites. The CYP3A A392G genotype was also associated with AUC24h. The CYP2B (G516T) T/T genotype was significantly associated with adverse CNS symptoms (p = 0.04). None of the genotypes studied showed significant associations with initial or short-term virologic or immunologic response to treatment.
The PK case studies showing therapeutic efavirenz levels three weeks after discontinuation of the NNRTI shows that extremely slow clearance may not be so unusual. The genetic research from the US studies supports particular caution in African patients.
- Ribaudo H, Clifford D, Gulick R et al. Relationships between efavirenz pharmacokinetics, side effects, drug discontinuation, virologic response, and race: results from ACTG A5095/A5097s. 11th CROI 2004, Abstract 132.
- Haas D, Ribaudo H, Kim R et al. A common CYP2B6 variant is associated with efavirenz pharmacokinetics and central nervous system side effects: AACTG Study NWCS214. 11th CROI 2004, Oral abstract 133.