Successful genotype-tailored treatment with small-dose efavirenz

Abstract

King and Aberg [1] recently published an excellent review of the clinical implications of population differences and genomic variations in efavirenz (EFV) treatment. They elegantly summarized the relationship between EFV concentration under standard dosage (600 mg once daily) and the genotype of cytochrome p450 2B6 (CYP2B6), a primary liver enzyme in EFV metabolism. They also highlighted the importance of CYP2B6 516 G>T SNP as a marker of individuals at risk of high EFV concentration and potential development of central nervous system (CNS) side-effects. However, it is desirable to discuss possible personalization of treatment by EFV dose modification. As we described in our recent clinical study [2], we reduced EFV dosage in 12 patients with CYP2B6 516G>T polymorphism who were found to have extremely high EFV concentrations when treated with the standard dosage. The dosage was reduced from 600 to 400 mg in five individuals and to 200 mg in seven, and their HIV-1 load was successfully suppressed below detection limit (50 copies/ml) at these dosages. Interestingly, nine of the 12 suffered from chronic CNS-related symptoms at the standard dosage, but these improved in all nine by EFV dose reduction. An example of these patients is a 71-year-old man who reported having nightmares almost every night since starting EFV-containing antiretroviral therapy at 600 mg 3 years ago (Fig. 1). Plasma EFV concentrations were extremely high and analysis of the 516G>T SNP showed CYP2B6 516 genotype T/T. The EFV dosage was reduced to 400 mg. This resulted in a dramatic change in dream contents from nightmares to pleasant dreams. These changes occurred although the EFV concentration remained high at 400 mg. Therefore, we further reduced the dose to 200 mg. The second reduction resulted in complete disappearance of dreams. Although he missed the dreams, the EFV concentration decreased to within the target range at 200 mg. The EFV dose has been at 200 mg for more than 2 years, and the HIV-1 load remains under detection limit.Fig. 1: Efavirenz dose reduction resulted in reduced efavirenz concentration and improved central nervous system related symptom. A CYP2B6 516T/T genotype holder reported having nightmares every night for 3 years, which disappeared after efavirenz (EFV) dose reduction.Hasse et al.[3] also reported a patient with genotype CYP2B6 516T/T, who had chronic CNS symptoms and extremely high EFV concentration at 600 mg dose, but the symptoms resolved by reducing the EFV dose to 200 mg. Considered together, the above report and our study suggest that the quality of life of CYP2B6 516T/T genotype holders who suffer from CNS-related symptoms can be improved by reducing EFV dose from the standard to 400 or even 200 mg. In their review, King and Aberg [1] indicated that the cost remains an issue for identifying CYP2B6 516 genotype. However, one Japanese commercial laboratory has already developed a CYP2B6 516 genotype detection system based on the Invader assay [4], which costs only ¥8000 (∼$75) per single test. Thus, the financial benefits of reducing EFV dosage should compensate for the cost of genotyping. Further large-scale studies are needed to discuss genotype-based tailored EFV treatment.