CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India

Abstract

The dose of efavirenz during concomitant rifampin (RMP) administration is a matter of debate. We studied the influence of RMP coadministration on the steady-state pharmacokinetics of efavirenz in human immunodeficiency virus type 1 (HIV-1)-infected patients in South India. Fifty-seven HIV-tuberculosis (TB)-coinfected and 15 HIV-1-infected patients receiving combination antiretroviral therapy (CART) with an efavirenz (600 mg once daily)-containing regimen were recruited. HIV-TB-coinfected patients were receiving treatment with RMP-containing regimens. A complete pharmacokinetic study was conducted with 19 HIV-TB patients on two occasions (with and without RMP). Trough concentrations of efavirenz were measured in the remaining 38 patients during RMP coadministration. The 15 HIV-infected patients underwent complete pharmacokinetic sampling on one occasion. Plasma efavirenz was estimated by high-performance liquid chromatography, and genotyping of CYP2B6 G516T polymorphism was performed by sequencing. Peak and trough concentrations and exposure to efavirenz were significantly higher in TT than in GT and GG genotype patients (P < 0.001). Although RMP coadministration decreased the peak and trough concentrations and exposure to efavirenz by 17.8, 20.4, and 18.6%, respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 g/ml) in 6 (8%) of 72 patients. In this South Indian population of HIV-infected patients, CYP2B6 G516T polymorphism but not RMP coadministration significantly influenced the pharmacokinetics of efavirenz; patients with the TT genotype had very high blood levels of efavirenz. While a small proportion of patients had subtherapeutic efavirenz levels, the clinical implications are uncertain, as all had good immunological responses to CART.Tuberculosis (TB) remains one of the most important opportunistic infections in human immunodeficiency virus (HIV)-infected individuals. The burden of effectively treating HIV-TB-coinfected patients is a well-recognized global public health problem. A decreased risk of death has been observed in patients starting combination antiretroviral therapy (CART) compared with those not receiving CART after the diagnosis of TB (2, 9, 13). In India, there are effective treatments available for both HIV disease and TB through the government program. Concomitant administration of CART and anti-TB medications is often complicated because of drug-drug interactions and the adverse-effect profile (17,30,36).Efavirenz (EFV) is a potent nonnucleoside reverse transcriptase inhibitor for the treatment of HIV type 1 (HIV-1) infection. EFV has been recommended as a first-line option in antiretroviral therapy (ART) and the preferential choice in TB-and HIV-coinfected patients, despite induction of the cytochrome P-450 system by rifampin (RMP). The available pharmacokinetic data provide evidence of a 13 to 25% reduction in EFV levels when it is coadministered with RMP (20), which is lower than those of nevirapine (40...

Effect of Rifampin and Rifabutin on the Pharmacokinetics of Lersivirine and Effect of Lersivirine on the Pharmacokinetics of Rifabutin and 25-O-Desacetyl-Rifabutin in Healthy Subjects

“…In one study, the change in efavirenz exposure following coadministration with rifampin ranged from a decrease of 65% to an increase of 37% (21), which suggests interindividual differences in enzyme activity. Furthermore, studies have shown that individuals with CYP2B6 516 TT genotypes are at risk of high efavirenz plasma exposures even in the presence of rifampin (20,29). However, efavirenz trough concentrations, the best predictor of virological activity, have been shown to remain above the concentration necessary to suppress HIV in vitro in patients on concomitant rifampin (22).…”

Impact of Pharmacogenetic Markers ofCYP2B6, Clinical Factors, and Drug-Drug Interaction on Efavirenz Concentrations in HIV/Tuberculosis-Coinfected Patients

“…The CYP2B6 gene is highly polymorphic (9,10). Most previous studies have shown CYP2B6 single nucleotide polymorphisms (SNPs), particularly 516GϾT, to be associated with high plasma concentrations of efavirenz and its drug-related toxicity (11)(12)(13). To date, data concerning these polymorphisms incorporated with clinical factors and drug-drug interactions that may be associated with low efavirenz concentrations are very limited.…”

Rifamycin Use in HIV-Infected Patients with Tuberculosis

“…African-Americans, Hispanics and Asians tend to have higher efavirenz concentrations than Caucasians. (Burger et al, 2006a;Ramachandran et al, 2009;Kwara et al, 2010) It is not clear if body weight is related to efavirenz plasma concentration or clearance, considering that studies have found contradictory results. Additional studies are needed regarding the impact of body weight, especially in patients weighing more than 60 kg.…”

“…(Ribera et al, 2001;Autar et al, 2005;Matteelli et al, 2009) However, a small study by Ramachandran et al noted that 8 out of 13 patients had blood concentrations under the C min (3 µg/mL). (Ramachandran et al, 2009) They proposed the use of a higher dose (300 mg) for providing therapeutic drug concentrations to those patients; however, the study was composed of a small number of patients and conducted in a short period of time. The effect of rifampin on nevirapine's concentrations seems to decrease over time when nevirapine is used chronically with anti-TB drugs.…”