Higher Sustiva Levels Seen in Some African-Americans
Drug metabolism is highly complex and may be modulated by interactions between multiple enzymes and environmental factors. Although the CYP3A4 enzyme responsible for clearing many protease inhibitors from the system is best known, new enzymes and new interactions continue to come to light. And for every new metabolic player discovered there is the potential for genetic variability between individuals and populations to complicate treatment decisions.
In a slide session at the 11th Annual Retrovirus Conference, Heather Ribaudo, of the Harvard School of Public Health, reported on a study of the pharmacokinetics of efavirenz conducted by the AIDS Clinical Trials Group (ACTG). The study, ACTG 5097s, found that clearance of efavirenz from the body was increased by 32% in non-Hispanic whites compared to blacks or Hispanics. She found a slight association between higher blood levels of efavirenz and study discontinuations, although these did not seem to relate to the incidence of CNS toxicity or to virologic response. An analysis of discontinuations by race/ethnicity was not performed. No association with gender was observed.
David Haas, of Vanderbilt University in Nashville, presented a genetic analysis of a subset of 89 individuals from the A5097s study. Haas found that a single nucleotide polymorphism (SNP) that changed the DNA code from a "G" to a "T" at position 516 of the gene for the CYP2B6 metabolic enzyme was associated with slower clearance of efavirenz, higher blood levels of the drug and more CNS-related side effects.
Median AUC (a measure of total drug exposure) of efavirenz levels was about 3 times higher with the CYP2B6 position 516 TT allele than with GG. But after controlling for these alleles, there was no association between race/ethnicity and efavirenz levels. The TT and GT alleles were also significantly associated with a greater number of CNS-related adverse events at the initiation of therapy, which gradually disappeared by 24 weeks, even though higher efavirenz levels persisted. However, there was no association with viral load response.
Overall, in the study and in a separate representative population sample of DNA, at least one G516T allele appeared in 21% of European-Americans and in 38% of African Americans. The double-dose TT allele occurred in about 20% of African-Americans but in only 3% of European Americans. The study also detected a number of SNPs in other metabolic enzymes, but none were as strongly associated with the blood levels of efavirenz. While having the TT allele might be expected to predict better efficacy of efavirenz, it may also contribute to higher discontinuation rates if side effects are more pronounced. Both of these require further analysis.
The CYP2B6 G516T SNP had not previously been recognized as a factor in efavirenz metabolism. This enzyme also metabolizes nevirapine, nicotine, tamoxifen, bupropion, diazepam and Ecstasy, so more study of its impact on individual dosing and the potential for drug-drug interactions should be followed-up. The effect of this polymorphism on nevirapine is most critical, since it is poised to become the most widely used antiretroviral drug in the world. Surveys of the frequency of the G516T allele in worldwide populations should be conducted right away, and analysis of Boehringer's extensive safety database should be done to look for correlations of toxicity with the SNP. Studies should also continue to evaluate if genetic testing for every known SNP affecting drug metabolism can help individualize therapy to avoid toxicity and maximize efficacy.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.