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PLoS One. 2014 Mar 7;9(3):e90350. doi: 10.1371/journal.pone.0090350. eCollection 2014.

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

Author information

  • 1Institut Pasteur du Cambodge, Epidemiology and Public Health Unit, Phnom Penh, Cambodia.
  • 2Institut Pasteur, Unité de Recherche et d'Expertise Epidémiologie des Maladies Emergentes, Paris, France.
  • 3ANRS, Ho Chi Minh City, Vietnam.
  • 4Faculty of Pharmacy, University of Health Sciences, Phnom Penh, Cambodia.
  • 5Khmer-Soviet Friendship Hospital, Phnom Penh, Cambodia.
  • 6Donkeo Provincial Hospital, Takeo, Cambodia; Médecins Sans Frontières, Phnom Penh, Cambodia.
  • 7Svay Rieng Provincial Hospital, Svay Rieng, Cambodia; Cambodian Health Committee, Phnom Penh, Cambodia.
  • 8Calmette Hospital, Phnom Penh, Cambodia.
  • 9Médecins Sans Frontières, Phnom Penh, Cambodia; Siem Reap Referral Hospital, Siem Reap, Cambodia.
  • 10Institut Pasteur du Cambodge, HIV/Hepatitis Laboratory, Phnom Penh, Cambodia.
  • 11Institut Pasteur, Unité de Recherche et d'Expertise Epidémiologie des Maladies Emergentes, Paris, France; Conservatoire National des Arts et Métiers, Paris, France.
  • 12Cambodian Health Committee, Phnom Penh, Cambodia.
  • 13Cambodian Health Committee, Phnom Penh, Cambodia; Program in Cellular and Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
  • 14Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud, Pneumology Department, Le Kremlin-Bicêtre, France; UMR INSERM 1087 CNRS UMR_6291, l'Institut du Thorax, Service de Pneumologie, CHU de Nantes, DHU2020, Université de Nantes, France.
  • 15Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud, Clinical Pharmacy Department, Le Kremlin-Bicêtre, France.

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.

PMID:
24608960
[PubMed - indexed for MEDLINE]
PMCID:
PMC3946522
Free PMC Article
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