Moderator effect of CYP2B6 genotype in HIV-1 patients with tuberculosis treated with rifampicin and efavirenz

Efavirenz (EFV) is the preferred non-nucleoside reverse transcriptase inhibitor component of the ARV regimen in HIV-TB patients. Concomitant use of EFV with rifampicin (RIF), an important component of first-line tuberculosis treatment, induces various hepatic cytochrome P450 enzymes and is known to decrease EFV plasma concentrations in healthy volunteers and HIV-1 patients and EFV plasma concentrations below 1,000 µg/mL have been associated with an increased risk of virological failure [1]. Moreover, previous studies have shown that inter-individual variability in EFV plasma concentrations are associated with the presence of allelic variants in CYP2B6 gene. Carriers of the T allele of polymorphism 516 G>T are reported to be associated with slower EFV oral clearance. The aim of our study was to determine the influence of CYP2B6 genotype in EFV levels in HIV patients with TB treated with RIF. Four HIV patients who started ARV treatment concomitantly with TB treatment were analyzed. These patients started a regimen based on EFV at doses higher than standard due to RIF interaction. Viral load, CD4+ cell count and plasma levels of EFV in plasma were measured at each visit, and genotyping for CYP2B6 (516G>T) polymorphism were performed. The self-reported rates of adherence to HAART were very high. One patient, who had TT genotype, required progressive dose reduction by toxic levels (C min : 20 µg/mL) and effects on the central nervous system. Dose was adjusted to 600 mg qd despite treatment with RIF, and he required even lower doses after completion of TB treatment, 400 mg qd. Two other patients with non-mutated genotype (GG) required dose escalation up to 1000 mg qd to achieve minimum recommended EFV concentrations between 1 and 4 µg/mL. All of them achieved virological suppression at six months. The fourth patient, who had non-mutated genotype, required dose increases for several months until dose adjustment. He needed 1600 mg qd during treatment with RIF. He presented virological failure, likely to maintain infratherapeutic levels of EFV for several months. Our study shows that the variability in EFV pharmacokinetic behaviour justifies the use of therapeutic drug monitoring (TDM) in situations in which there are potential interactions with other drug. Also, it is recommended to know CYP2B6 genotype in patients receiving HIV-TB to predict their metabolizing behaviour. TDM in clinical practise continues to be the best tool for optimizing the dosing of EFV. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection De la Calle C et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18364 http://www.jiasociety.org/index.php/jias/article/view/18364 | http://dx.doi.org/10.7448/IAS.15.6.18364