Abstract

ObjectiveTo assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients.MethodsHIV-infected adults with CD4+ T cell count ≤200/mm3 received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis.ResultsEfavirenz plasma concentrations were available in 540 patients. Median [interquartile range] efavirenz concentrations were 2,674 ng/mL [1,690–4,533], 2,667 ng/mL [1,753–4,494] and 2,799 ng/mL [1,804–4,744] at week +2, week +6, week 22, respectively, and 2,766 ng/mL [1,941–3,976] at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p<0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p<0.001) and of hepatotoxicity (p<0.001).ConclusionBody weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity.Trial RegistrationClinicalTrials.gov NCT01300481

Highlights

  • Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in combination with nucleoside reverse transcriptase inhibitors as first-line treatment of HIV-1 infection

  • The CAMELIA (ANRS 1295-CIPRA KH001) randomized clinical trial showed a 34% reduction of mortality in severely immunocompromised HIV-infected adults treated for tuberculosis when efavirenz-containing antiretroviral therapy (ART) was initiated two weeks compared to eight weeks after tuberculosis treatment onset [11]

  • We investigated risk factors associated with efavirenz concentrations below the therapeutic range and we analyzed the association between efavirenz exposure and efficacy and toxicity

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Summary

Introduction

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in combination with nucleoside reverse transcriptase inhibitors as first-line treatment of HIV-1 infection. Efavirenz-containing ART is the first-line treatment recommended by the World Health Organization (WHO) in HIV-infected patients, especially when treated concurrently with tuberculosis treatment including rifampicin and isoniazid for 6 months and ethambutol and pyrazinamide for the first 2-months [2]. The CAMELIA (ANRS 1295-CIPRA KH001) randomized clinical trial showed a 34% reduction of mortality in severely immunocompromised HIV-infected adults treated for tuberculosis when efavirenz-containing ART was initiated two weeks compared to eight weeks after tuberculosis treatment onset [11]. We describe plasma concentrations of efavirenz over one year of follow-up on and off tuberculosis treatment in 540 patients included in the CAMELIA trial. We investigated risk factors associated with efavirenz concentrations below the therapeutic range and we analyzed the association between efavirenz exposure and efficacy and toxicity

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