Article

Plasma concentrations of efavirenz with a 600 mg standard dose in Cambodian HIV-infected adults treated for tuberculosis with a body weight above 50 kg.

Epidemiology and Public Health Unit, Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
Antiviral therapy (Impact Factor: 3.14). 12/2012; 18(3). DOI: 10.3851/IMP2483
Source: PubMed

ABSTRACT BACKGROUND: The optimal dose of efavirenz for HIV-infected patients receiving a tuberculosis regimen including rifampicin remains debated, especially for subjects weighing over 50 kg. To address this issue, we measured plasma efavirenz concentrations from Cambodian adults with tuberculosis enrolled in the CAMELIA randomized trial (ClinicalTrials.gov number, NCT01300481) six weeks after the onset of antiretroviral therapy. METHODS: Efavirenz concentrations and proportions of patients with concentrations below 1000 ng/mL were compared across patient body weight below or above 50 kg using a Student's t-test and a chi-squared test, respectively. Factors associated with efavirenz concentrations below 1000 ng/mL were identified by logistic regression analysis. Logistic regression analysis was also performed to check if efavirenz concentrations below 1000 ng/mL were associated with virological failure. RESULTS: Plasma efavirenz concentrations were higher in the 332 patients who weighed less than 50 kg compared to the 150 who weighed more than 50 kg (median [IQR]: 2859 [1787-4749] and 2060 [1425-3575] ng/mL, respectively; p=0.02). However, the proportion of patients with efavirenz concentrations below 1000 ng/mL was not different between those weighing less than or more than 50 kg (6% and 10%, respectively; p=0.13) and a body weight above 50 kg was not associated with a higher risk of plasma efavirenz concentrations below 1000 ng/mL. When plasma efavirenz concentrations below 1000 ng/mL were present, they were not associated with virological failure. CONCLUSION: The current WHO guidelines recommending 600 mg efavirenz daily irrespective of patient's body weight remains a safe and effective approach to treating co-infected adults needing simultaneous tuberculosis and HIV therapy.

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    ABSTRACT: We investigated the population pharmacokinetics and pharmacogenetics of efavirenz in 307 patients coinfected with human immunodeficiency virus and tuberculosis and included in the Cambodian Early vs Late Initiation of Antiretrovirals trial (CAMELIA) in Cambodia. Efavirenz (600 mg/d) and stavudine plus lamivudine were ad-ministered in addition to standard antituberculosis treatment, including rifampicin and isoniazid. Blood samples were obtained a mean of 14 hours after efavirenz intake at weeks 2 and 6 after initiation of efavirenz and weeks 22 (efavirenz plus antituberculosis drugs) and 50 (efavirenz alone) after initiation of antituberculosis treatment. Ten patients participated in an extensive pharmacokinetic study after week 50. CYP2B6 G516T and C485-18T polymorphisms were the most significant covariates, with weight showing a significant minor effect. Change in efavirenz apparent clearance in patients taking both efavirenz and antituberculosis treatment was highly dependent on NAT2 polymorphism, as a possible surrogate of isoniazid exposure. Patients carrying the CYP2B6 516 TT genotype and slow-acetylation NAT2 phenotype had the lowest efavirenz apparent clearance. These data suggest that the inducing effect of rifampicin is counterbalanced by a concentration-dependant in-hibitory effect of isoniazid on efavirenz clearance. Efavirenz is a nonnucleoside reverse-transcriptase inhib-itor of human immunodeficiency virus (HIV) type 1 and one of the preferred components of the first-line an-tiretroviral treatment (ART) regimen of HIV infection worldwide. Current guidelines recommend efavirenz at a dosage of 600 mg/d combined with 2 nucleoside (or nucleotide) analogues as one of the preferred options for first-line therapy in developed as well as resource-limited countries [1]. Furthermore, it was demonstrated that efavirenz can be coadministered safely with stan-dard antituberculosis therapy that includes rifampicin, a potent drug enzyme inducer, and isoniazid for 6 months and ethambutol plus pyrazinamide for the first 2 months. Earlier studies recommended increasing the efavirenz dosage to 800 mg/d in patients receiving efa-virenz and rifampicin concomitantly [2, 3]. Later studies demonstrated the efficacy of efavirenz at a dosage of 600 mg/d along with antituberculosis drugs [4]; recently, it has been suggested that the efavirenz dosage be in-creased to 800 mg/d in patients weighing >50 kg [5]. Efavirenz is metabolized mainly through CYP2B6 [6], which has been demonstrated to be inducible

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