title: 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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01300481.
authors.affiliation: Institut Pasteur du Cambodge, Epidemiology and Public Health Unit, Phnom Penh, Cambodia.
authors.forename: Laurence
authors.initials: L
authors.lastname: Borand
authors.affiliation: Institut Pasteur, Unité de Recherche et d'Expertise Epidémiologie des Maladies Emergentes, Paris, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Madec
authors.affiliation: ANRS, Ho Chi Minh City, Vietnam.
authors.forename: Didier
authors.initials: D
authors.lastname: Laureillard
authors.affiliation: Faculty of Pharmacy, University of Health Sciences, Phnom Penh, Cambodia.
authors.forename: Monidarin
authors.initials: M
authors.lastname: Chou
authors.affiliation: Institut Pasteur du Cambodge, Epidemiology and Public Health Unit, Phnom Penh, Cambodia.
authors.forename: Olivier
authors.initials: O
authors.lastname: Marcy
authors.affiliation: Institut Pasteur du Cambodge, Epidemiology and Public Health Unit, Phnom Penh, Cambodia.
authors.forename: Phearavin
authors.initials: P
authors.lastname: Pheng
authors.affiliation: Khmer-Soviet Friendship Hospital, Phnom Penh, Cambodia.
authors.forename: Narom
authors.initials: N
authors.lastname: Prak
authors.affiliation: Donkeo Provincial Hospital, Takeo, Cambodia; Médecins Sans Frontières, Phnom Penh, Cambodia.
authors.forename: Chindamony
authors.initials: C
authors.lastname: Kim
authors.affiliation: Svay Rieng Provincial Hospital, Svay Rieng, Cambodia; Cambodian Health Committee, Phnom Penh, Cambodia.
authors.forename: Khemarin Kim
authors.initials: KK
authors.lastname: Lak
authors.affiliation: Calmette Hospital, Phnom Penh, Cambodia.
authors.forename: Chanroeun
authors.initials: C
authors.lastname: Hak
authors.affiliation: Médecins Sans Frontières, Phnom Penh, Cambodia; Siem Reap Referral Hospital, Siem Reap, Cambodia.
authors.forename: Bunnet
authors.initials: B
authors.lastname: Dim
authors.affiliation: Institut Pasteur du Cambodge, HIV/Hepatitis Laboratory, Phnom Penh, Cambodia.
authors.forename: Eric
authors.initials: E
authors.lastname: Nerrienet
authors.affiliation: Institut Pasteur, Unité de Recherche et d'Expertise Epidémiologie des Maladies Emergentes, Paris, France; Conservatoire National des Arts et Métiers, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Fontanet
authors.affiliation: Cambodian Health Committee, Phnom Penh, Cambodia.
authors.forename: Thim
authors.initials: T
authors.lastname: Sok
authors.affiliation: Cambodian Health Committee, Phnom Penh, Cambodia; Program in Cellular and Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Goldfeld
authors.affiliation: Assistance 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.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Blanc
authors.affiliation: Assistance Publique - Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud, Clinical Pharmacy Department, Le Kremlin-Bicêtre, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Taburet
mesh_terms: D000328:Adult; D000480:Alkynes; D048588:Benzoxazines / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001835:Body Weight; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002160:Cambodia; D060085:Coinfection / Q000097:blood / Q000188:drug therapy; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D008297:Male; D018894:Reverse Transcriptase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014376:Tuberculosis / Q000097:blood* / Q000188:drug therapy*
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz