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 ( 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: Plasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese. HIV-infected patients with or without TB who had received combination antiretroviral therapy containing efavirenz (600 mg daily) for two weeks or greater were enrolled for determinations of CYP2B6 G516T polymorphism and plasma efavirenz concentrations with the use of polymerase-chain-reaction restriction fragment-length polymorphism and high-performance liquid chromatography, respectively. From October 2009 to August 2012, 171 HIV-infected patients, including 18 with TB, were enrolled 113 (66.1%) with CYP2B6 G516G, 55 (32.2%) GT, and 3 (1.8%) TT genotype. Patients receiving rifampicin had a significantly lower median plasma efavirenz concentration than the control group (2.16 vs 2.92 mg/L, P = 0.003); however, all patients achieved target plasma concentration (>1 mg/L). Patients with GT or TT genotype had a significantly higher plasma concentration than those with GG genotype (2.50 vs 3.47 mg/L for GT genotype and 8.78 mg/L for TT genotype, P<0.001). Plasma efavirenz concentration >4 mg/L was noted in 38 (22.2%) patients, which was associated with a lower weight (per 10-kg increase, odds ratio, 0.52; 95% confidence interval, 0.33-0.83) and GT or TT genotype (odds ratio, 4.35; 95% confidence interval, 1.97-9.59) in multivariate analysis. Despite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB who receive efavirenz 600 mg daily. Carriage of CYP2B6 516 GT and TT genotypes and a lower weight are associated with higher plasma efavirenz concentrations.
    PLoS ONE 02/2014; 9(2):e88497. DOI:10.1371/journal.pone.0088497 · 3.53 Impact Factor
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    ABSTRACT: The syndemic of human immunodeficiency virus (HIV)/tuberculosis (TB) co-infection has grown as a result of the considerable sociogeographic overlaps between the two epidemics. The situation is particularly worrisome in countries with high or intermediate TB burden against the background of a variable HIV epidemic state. Early diagnosis of TB disease in an HIV-infected person is paramount but suffers from lack of sensitive and specific diagnostic tools. Enhanced symptom screening is currently advocated, and the wide application of affordable molecular diagnostics is urgently needed. Treatment of TB/HIV co-infection involves the concurrent use of standard antiretrovirals and antimycobacterials during which harmful drug interaction may occur. The pharmacokinetic interaction between rifamycin and antiretrovirals is a case in point, requiring dosage adjustment and preferential use of rifabutin, if available. Early initiation of antiretroviral therapy is indicated, preferably at 2 weeks after starting TB treatment for patients with a CD4 of
    Respirology 08/2013; 18(6). DOI:10.1111/resp.12120 · 3.50 Impact Factor
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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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May 26, 2014