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

Abstract

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/mm(3) 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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01300481.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 9 Issue 3 Pg. e90350 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24608960 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alkynes
• Benzoxazines
• Cyclopropanes
• Reverse Transcriptase Inhibitors
• efavirenz

Topics

• Adult
• Alkynes
• Benzoxazines (blood, pharmacokinetics, therapeutic use)
• Body Weight
• CD4-Positive T-Lymphocytes (metabolism)
• Cambodia
• Coinfection (blood, drug therapy)
• Cyclopropanes
• Female
• HIV Infections (blood, drug therapy)
• Humans
• Male
• Reverse Transcriptase Inhibitors (blood, pharmacokinetics, therapeutic use)
• Tuberculosis (blood, drug therapy)