Plasma Concentrations, Efficacy and Safety of Efavirenz in HIV-Infected Adults Treated for Tuberculosis in Cambodia (ANRS 1295-CIPRA KH001 CAMELIA Trial)

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

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

“…However, plasma concentration median in our study population was higher than all others studies conducted in Africa, which is very close to that found by Gounden et al (3,980 µg/L) in South Africa [12]. But the median observed in our study was strangely higher than those found by Sarfo et al (1,087 µg/L) or Gunda et al (2,112 µg/L) respectively in Ghana and Tanzania [13][14]. Plasma concentration average of our population was 6,360 µg/L ± 539 µg/L.…”

Prospective plasma efavirenz concentration assessment in Chinese HIV‐infected adults enrolled in a large multicentre study

“…By contrast, a study of 80 South African patients, with a median efavirenz concentration of 3.98 mg/L, found that the proportion of patients with high efavirenz concentrations was 40% . Another study with 540 Cambodian patients, with a median (IQR) efavirenz concentration at week 50 of 2.77 (1.94, 3.98) mg/L, found that proportion to be 20–30% . A recent study from Taiwan reported a median efavirenz concentration (IQR) of 2.82 (0.98–10.00) mg/L, and 22.2% of subjects had high efavirenz concentrations after at least 2 weeks of efavirenz treatment.…”

“…In our cohort, the median plasma efavirenz concentration increased from 3.02 to 3.71 mg/L from week 4 to week 48; such findings were not reported in previous studies , and the mechanism of such an increase over time remains unclear. We speculate that one possibility is improved adherence over time.…”

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

“…Efforts to predict safety and efficacy of EFV have focused on characterizing the systemic pharmacokinetics (12,22,23). Borand et al (24) found no association between treatment failure and the recommended efavirenz concentrations in plasma below 1 mg/liter (6). This may suggest that a lack of knowledge of the relationship between plasma and intracellular concentrations of EFV limits the ability to fully understand the pharmacokinetic-pharmacodynamic relationships of EFV and to predict treatment and toxicity outcomes.…”