The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva) is generally well tolerated, but causes central nervous system (CNS) side effects symptoms such as dizziness and abnormal dreams in some individuals.

As reported in the November 1, 2007 issue of Clinical Infectious Diseases, Japanese researchers conducted a study to assess whether genotypic testing could help determine which patients could safely reduce their efavirenz dose in an effort to minimize adverse events.

Efavirenz is metabolized primarily by the liver enzyme cytochrome P450 2B6 (CYP2B6), the authors noted as background. High plasma concentrations of the drug -- linked to frequent CNS side effects -- are associated with a G-to-T polymorphism at position 516 (516G-to-T) of CYP2B6.

The researchers determined CYP2B6 genotypes for 456 HIV-infected patients who were receiving or scheduled to receive efavirenz-containing regimens. The efavirenz dose was reduced in carriers of the CYP2B6 516G-to-T mutation who had high plasma efavirenz concentrations while receiving the standard dosage (600 mg). Efavirenz-naive homozygous CYP2B6 516G-to-T carriers were treated with low-dose efavirenz. In both groups, the dose was further reduced if plasma efavirenz concentrations remained high.

Results

·         CYP2B6 516G-to-T was identified in the *6 allele (found in 17.9% of subjects) and in a novel allele, *26 (found in 1.3%).

·         All efavirenz-treated CYP2B6 *6/*6 and *6/*26 carriers had extremely high plasma efavirenz concentrations (>6000 ng/mL) while receiving the standard dosage.

·         The efavirenz dose was reduced to 400 mg for 11 patients and to 200 mg for 7 patients with persistently suppressed HIV RNA levels.

·         Efavirenz-containing treatment was initiated at 400 mg in 4 homozygous CYP2B6 *6/*6 carriers and one *6/*26 carrier.

·         2 of these individuals still had a high plasma efavirenz concentration while receiving this dose;

·         These patients maintained HIV suppression when the dose was further reduced to 200 mg.

·         CNS symptoms improved with dose reduction in 10 of 14 patients, though they continued to experience some degree of sleep disturbance.

Conclusion

Based on these findings, the study authors concluded, “Genotype-based efavirenz dose reduction is feasible in CYP2B6 *6/*6 and *6/*26 carriers, which can reduce efavirenz-associated CNS symptoms.”

10/26/07

Reference