Individual Genetic Variations, Rather than Race/Ethnicity, Best Predict Efavirenz (Sustiva) Side Effects

By Liz Highleyman

Research is increasingly revealing a link between genetic characteristics and response to medical therapies, ushering in an era of individually tailored treatment based on pharmacogenomics.

In the field of HIV, studies have shown that individuals with the HLA-B*5701 genetic variation are more likely to experience abacavir hypersensitivity reactions. While the overall hypersensitivity rate is about 5%, the likelihood is significantly higher in people of Northern European ancestry compared with those of African descent.

Conversely, blacks are more likely to have a genetic variation that affects processing of efavirenz (Sustiva, also in the Atripla coformulation), which can result in altered blood levels and more intense side effects.

While race/ethnicity is often used to categorize patients in clinical trials, it is too crude to predict which specific individuals will develop side effects. While genetic characteristics occur with differing frequencies in various racial groups, they are rarely exclusive to a given group given centuries of mixing among populations.

Jennifer King of the University of Alabama at Birmingham and Judith Aberg of
New York University School of Medicine discussed this issue with respect to choosing non-nucleoside reverse transcriptase inhibitors (NNRTIs) in an editorial review in the September 12, 2008 edition of AIDS.

The authors reviewed and summarized data from prior published studies looking at the effect of race/ethnicity and genetic variations on efavirenz blood concentrations, efficacy, and side effects.

Overall, most studies did not find significant differences in efavirenz efficacy or toxicity across whites, blacks, and Hispanics. However, some studies have observed an association between variations in the CYP2B6 gene -- which controls an enzyme in the liver that processes the drug -- and altered efavirenz metabolism.

Although data are not consistent, people with the CYP2B6*6 variation (indicated by the 516G>T single nucleotide polymorphism, or the T/T genotype) tend to have higher efavirenz blood concentrations soon after starting the drug and potentially worse central nervous system side effects such as anxiety or unusual dreams. Most studies show that the T/T genotype is more common among than among whites (for example, 20% of African-Americans vs 3% of European-Americans in one study).

One study found that median efavirenz concentrations were 1.71 mg/mL in people with the usual G/G genotype, 2.6 mg/mL in those with the heterozygous G/T genotype, and 3.57 mg/mL in those with the T/T genotype. Another research team found that efavirenz plasma clearance was 54% lower in individuals with the T/T genotype relative to G/G.

Polymorphisms of the MDR1 gene encoding P-glycoprotein, which transports drugs in the body, may be associated with lower efavirenz levels, though here data are even more mixed.

Based on their analysis, King and Aberg concluded that decisions about whether to use efavirenz should not be made on the basis of race/ethnicity, although individual testing for specific genetic variants may hold promise.

"As with many antiretroviral medications, efavirenz is subject to interindividual variation in metabolism, effectiveness, and tolerability," they wrote. "Demographic factors such as age, sex, and ethnicity have been demonstrated to influence this variability, but other underlying factors such as genetics, disease state, and concomitant drug use can also play a role."

"The clinical impactions of these factors are only beginning to be understood," they continued. "Although significant advances have led to a greater understanding of interactions between genetic and host factors that influence the efficacy and toxicity of efavirenz, providers should not withhold treatment of HIV infection with an efavirenz-based regimen on the basis of racial or ethic categorizations."

10/10/08

Reference
J King and J Aberg. Clinical impact of patient population differences and genomic variation in efavirenz therapy. AIDS 22(14):1709-1717, September 12, 2008. (Abstract).