Laboratoire Rodolphe Mérieux de Phnom Penh

Plasma concentrations, efficacy and safety of efavirenz in HIV-infected adults treated for tuberculosis in Cambodia (ANRS 1295-CIPRA KH001 CAMELIA Trial)

Laurence Borand, Yoann Madec, Didier Laureillard, Monidarin Chou, Olivier Marcy, Phearavin Pheng, Narom Prak, Chindamony Kim, Khemarin Kim Lak, Chanroeun Hak, Bunnet Dim, Eric NERRIENET, Arnaud Fontanet, Thim Sok, Anne E. Goldfeld, François-Xavier Blanc, Anne-Marie TABURET

PLoS ONE 9(3): e90350. doi:10.1371/journal.pone.0090350


Objective: To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients.
Methods: HIV-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.
Results: Efavirenz 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).
Conclusion: Body 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.

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