Further genetic link to efavirenz absorption
Simon Collins, HIV i-Base
Further relevance to genetics and efavirenz (EFV) absorption were presented in a late breaker poster by Novoa and colleagues from Hospital Carlos III, Madrid.
Over 100 consecutive Caucasian adherent patients on EFV-containing combinations for over one month were studied with reference to codon 516 of the CYP2B6 isoenzyme. Median age was 40 years and 36% were coinfected with HCV. 80% patients were men and 20% were women.
Genotyping showed 52% were wild-type GG (39 men, 13 women); 43% carried the heterozygote GT mutation associated with African patients, slower drug clearance and higher drug concentrations (36 men, 7 women); and 5% carried homogygote TT mutations (5 men). Mid-dose drug levels were measured by HPLC at 12 weeks,
The study identified a wide range of interpatient variability in efavirenz levels (0.33-6.88ug/mL, target range = 1.0-4.0 ug/mL). Median plasma levels were higher in patients with 516 polymorphism and highest in patients with homogygote TT variant. All patients with sub-therapeutic levels had the wild-type GG. 19% and 40% of patients with GT and TT variants respectively had drug levels > 4ug/mL associated with higher toxicity.
Effect of genotype on efavirenz absorption
|Median (IQR) EFV levels (ug/mL)||1.71 (1.09-2.53)||2.6 (1.73-3.50)||3.57(2.55-6.07)|
|% sub-optimal (<1ug/mL)||19%||2%||0%|
|% toxicity (>4ug/mL)||5%||19%||40%|
Neither age, gender or HCV coinfection, were associated with different efavirenz levels.
This supports earlier findings presented by two different groups at the Retrovirus conference earlier this years (see HTB Vol5No3, April 2004). Those studied highlighted the risk for higher efavirenz exposure in African of African/American patients, referring to both toxicity and risk for resistance due to extended periods of monotherapy on stopping efavirenz-based combinations.
The significance prevalence of GT and TT variants in these Caucasian Spanish patients indicates a higher influence of genetic factor for tolerance or efficacy than is probably so far recognised.
The Novoa study is difficult to interpret since one third of the patients had Hepatitis B. However there appears to be a gene-dose effect TT>GT>GG.
Since genetic variation will have different effects on different populations, it is important to replicate these studies in diverse populations.
Novoa SR et al. Prediction of efavirenz plasma levels by determining the G516T polymorphism at the CYP2B6 isoenzyme – clinical implications. 41st ICAAC, Washington, 2004. Abstract H-584a.