Median Efavirenz Concentrations Research Articles

Severe efavirenz associated neurotoxicity: A retrospective cohort study.

Efavirenz (EFV) is associated with neuropsychiatric symptoms. Severe neurotoxicity has been reported but the clinical phenotype and risk factors are poorly defined. To characterise clinical presentations, risk factors and outcomes to help clinicians recognise severe neurotoxicity earlier. The authors retrospectively identified adults with supratherapeutic EFV concentrations (> 4 mg/L) obtained during routine clinical care in Cape Town, South Africa. Clinical and laboratory data at the time of EFV quantification were extracted from medical records. Logistic regression was performed to identify associations with neuropsychiatric symptoms, and with severe neurotoxicity. Eighty one patients were included; 62 with neuropsychiatric manifestations (most frequently ataxia [n = 20] and psychomotor slowing [n = 24]); and 19 with hepatotoxicity. Overall, 28 (34.6%) were male, 49 (60.5%) had concomitant isoniazid exposure, and median EFV concentration was 12.1 mg/L (interquartile range [IQR]: 6.6-20.0). Neuropsychiatric symptoms were associated with longer duration of EFV therapy, adjusted odds ratio (aOR) 1.3/180-day increment (95% confidence interval [CI]: 1.0-1.7); higher EFV concentrations, aOR 1.2/1 mg/L increase (95% CI: 1.0-1.4) and isoniazid exposure, aOR 8.2 (95% CI: 2.5-26.7). Severe neuropsychiatric symptoms occurred in 47 (75%) patients at a median of 5.9 months (IQR: 2.1-40.8) after EFV initiation. Severe symptoms odds were 1.2-fold higher (95% CI: 1.1-1.4) per 1 mg/L increase in EFV concentration. Symptoms resolved completely within 1 month in 25 (76%) patients with severe neurotoxicity who discontinued EFV. A concentration-effect relationship for severe neurotoxicity exists, which occurred late and resolved in most patients after EFV discontinuation. The authors highlighted clinical heterogeneity and morbidity of EFV-associated neurotoxicity.

Pharmacodynamics of efavirenz 400 mg in treatment-na\xefve Chinese HIV-infected patients in a prospective cohort study

BackgroundThe plasma concentration of patients treated with efavirenz (EFV) 600 mg was found to exceed the upper limit of the proposed therapeutic window in most Chinese HIV-infected individuals; thus, dosage reduction of EFV to 400 mg daily warranted consideration. This study aimed to assess the pharmacodynamics of EFV 400 mg for HIV-1-infected patients in China.MethodTwenty cART-naïve individuals were enrolled in this study. EFV 400 mg combined with tenofovir (TDF) and lamivudine (3TC) as an initial antiretroviral regimen was administered for 48 weeks. EFV concentration and T cell subsets as well as HIV RNA load were evaluated at baseline and at 4, 12, 24, and 48 weeks. Moreover, neuropsychiatric adverse effects were also assessed by the Hamilton depression (HAMD) scale and Pittsburgh sleep quality index (PSQI).ResultsEighteen males and two females whose median age was 26 (interquartile range [IQR]: 23–32) years completed 48 weeks of follow-up. The median EFV concentrations were 1.88 (IQR: 1.54–2.42), 1.74 (IQR: 1.36–1.93), 1.93 (IQR: 1.66–2.22), and 1.85 (IQR: 1.54–2.14) mg/L at weeks 4, 12, 24, and 48, respectively. The viral load was 4.59 (IQR: 4.10–5.19) log10 copies/mL at baseline, and it decreased by 4.6 (IQR: 3.98–5.18) log10 copies/mL from baseline to week 48. Three of 20 (15%), 10 of 20 (50.0%), 17 of 20 (85%), and 18 of 19 (95%) participants had a plasma viral load less than 50 copies/mL at weeks 4, 12, 24, and 48, respectively. The median CD4 cell count was 330 (IQR: 237–410) cells/μL at baseline, and it increased to 473 (IQR: 344–574) cells/μL at 48 weeks. The HAMD score was 5 (IQR: 3–9.8) and 3 (IQR: 2.25–4) at baseline and 48 weeks, respectively. The PSQI score was 4 (IQR: 2–5.8) and 3 (IQR: 2–4) at baseline and 48 weeks, respectively. Dizziness was the most common event, occurring in 70% of patients within the first 2 weeks of treatment.ConclusionPatients prescribed with EFV 400 mg-containing agents demonstrated favourable virological and immunological responses. And the plasma EFV concentration was within the recommended therapeutic range, with fewer adverse reactions than with EFV 600 mg. EFV 400 mg was effective and safe in Chinese HIV-infected patients.Trial registrationNCT04596488; Registered 21 October, 2020; Retrospectively registered.

Clinical phenotype and risk factors for severe efavirenz-associated neurotoxicity amongst inpatients in Cape Town, South Africa

Background: Efavirenz, widely used as first line antiretroviral therapy (ART), is frequently associated with mild transient neuropsychiatric symptoms, usually occurring early in therapy. More severe neurotoxicity has been reported, but the clinical phenotype and risk factors are poorly defined. Methods and materials: We identified adult patients with an efavirenz concentration >4 mg/L (target 1–4 mg/L) at four hospitals in Cape Town, South Africa. Data were extracted from medical records, including clinical symptoms and signs and laboratory abnormalities at the time of efavirenz quantification; severe neurotoxicity was defined as Division of AIDS score > 3. We performed logistic regression to identify associations with neuropsychiatric symptoms and severe neurotoxicity. Results: Data were included from 82 patients: 62 had neuropsychiatric symptoms, 19 had hepatitis, and 1 had no apparent indication for efavirenz quantification. Median age was 38 years (interquartile range (IQR) 29–45), median weight 53 kg (IQR 44–63), 29 (34%) were male, and 49 (63%) patients had concomitant isoniazid exposure. Median efavirenz concentration was 12.1 mg/L (IQR 6.6–20.0). Neuropsychiatric manifestations included ataxia (n = 20) and other cerebellar signs (n = 13), psychomotor slowing (n = 24), psychosis (n = 17), mood disturbance (n = 11), and insomnia/sleep disturbance (n = 4). Compared with hepatitis, neurotoxicity was associated with male sex (adjusted odds ratio (aOR) 20.0, 95% CI 2.0–199.9), higher efavirenz concentrations (aOR 1.2 per 1 mg/L increase, 95% CI 1.0–1.4) and isoniazid exposure (aOR 5.1, 95% CI 1.1–23.5). Severe neuropsychiatric symptoms occurred in 47 (75%) patients with neurotoxicity, after a median of 25 weeks (IQR 9–175) on efavirenz-based ART. Median efavirenz concentration was 20.0 mg/L (the upper limit of assay detection, IQR 13.0–20.0) in those with severe versus 7.0 mg/L (4.5–11.8) in those with mild neurotoxicity (p < 0.01). Amongst patients with severe neurotoxicity, there was complete resolution of symptoms within 1 month in 29/31 (94%) who discontinued efavirenz and in 2/5 (40%) who underwent dose-reduction. 3-month mortality was 11% (n = 45) for patients with severe neurotoxicity. Conclusion: Cerebellar signs were the most frequent clinical manifestation of efavirenz-associated neurotoxicity. There was a concentration-effect relationship for severe neurotoxicity, which occurred late and resolved in most patients after efavirenz discontinuation.

Correlation of hair and plasma efavirenz concentrations in HIV-positive South Africans.

BackgroundAntiretroviral concentrations in hair provide a longer window of drug detection and are useful for measuring longer-term drug exposure. Efavirenz is an important component of first-line treatment in resource-limited settings, but its concentrations in hair have not been well studied.MethodsThis study is a supplementary to a randomised controlled trial of an adherence intervention using an electronic adherence measuring device. Hair and plasma samples were collected from human immunodeficiency virus-positive patients in Cape Town, South Africa. Previously validated liquid chromatography tandem mass spectrometry methods were used to measure efavirenz concentrations in the collected hair and plasma samples. CYP2B6 genotyping of participants was also performed. Data analysis was performed using descriptive and comparative statistics as well as regression modelling.ResultsHair samples were collected from 59% of patients enrolled in the parent study. Results indicated that hair efavirenz concentrations were significantly influenced by participants’ CYP2B6 metaboliser status. Median efavirenz concentrations for extensive, intermediate and slow metaboliser genotypes were 3.54 ng/mg, 5.11 ng/mg and 10.66 ng/mg, respectively. A strong correlation was observed between the efavirenz concentrations measured in hair and plasma samples (Spearman’s correlation coefficients, 0.672–0.741, p < 0.0001). No relationship between hair efavirenz concentrations and virological failure or adherence measured using an electronic adherence was shown.ConclusionThe results from this study provide further insight into the potential of using hair as a matrix for measuring antiretroviral concentrations. However, challenges experienced in collecting hair samples suggest that this adherence measure may have limited utility in an African population.

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

Few studies have explored the optimal dosing for efavirenz in individuals from China. We investigated plasma efavirenz concentrations and their association with efficacy and tolerance of efavirenz 600mg daily in Chinese HIV-infected adults. An analysis was performed using plasma samples from 455 patients enrolled in a prospective multicentre trial in China. A total of 1198 plasma samples collected at weeks 4, 24 and 48 following antiretroviral therapy initiation were analysed. The mid-dose interval efavirenz concentrations (C12 ) were determined using high-performance liquid chromatography. The median efavirenz concentration (interquartile range) steadily increased over time from 3.02 (2.28-4.23) to 3.71 (2.91-4.91)mg/L from week 4 to 48 (P<0.001). The proportion of patients with C12 >4.0mg/L also rose from 28.0% to 34.2% and 43.8%, measured at 4, 24 and 48weeks, respectively (P<0.001). Five patients had efavirenz concentrations <1.0mg/L at week 4, 24 or 48. In the multivariable regression analysis, lower body weight and non-Han ethnicities were associated with higher efavirenz concentrations over time. At each time-point, patients with a body weight <60kg had significantly higher efavirenz C12 compared with those with body weight ≥60kg (P<0.05). Efavirenz concentrations increased steadily over 48weeks, and a substantial proportion of participants had efavirenz C12 above the upper limit of the proposed therapeutic window, especially those with low body weight (<60kg). Based upon these findings, a dosage reduction of efavirenz to 400mg daily may warrant consideration in this population, especially for those with lower body weight.

Effect of mid-dose efavirenz concentrations and CYP2B6 genotype on viral suppression in patients on first-line antiretroviral therapy

The therapeutic range for efavirenz plasma concentrations is unclear and some studies found no correlation with viral non-suppression. Efavirenz concentrations are variable, driven in part by polymorphisms in CYP2B6. We hypothesised that efavirenz mid-dosing concentrations, together with CYP2B6 metaboliser genotype, could predict viral non-suppression. Participants starting first-line efavirenz-based antiretroviral therapy were monitored for 48 weeks. HIV-RNA and efavirenz mid-dose interval concentrations were determined at Weeks 16 and 48. CYP2B6 metaboliser genotype status was determined by 516G→T and 983T→C polymorphisms. Cox proportional hazards modelling was used to predict viral non-suppression and to determine the most predictive efavirenz mid-dosing concentration threshold. In total, 180 participants were included. Median efavirenz concentrations were 2.3 mg/L (IQR 1.6–4.6 mg/L) and 2.2 mg/L (IQR 1.5–3.9 mg/L) at Weeks 16 and 48, respectively. Moreover, 49 (27.2%), 84 (46.7%) and 39 (21.7%) participants had extensive, intermediate or slow CYP2B6 metaboliser genotype, respectively. Log2 efavirenz concentrations [adjusted hazard ratio (aHR) = 0.77, 95% CI 0.67–0.89] and baseline CD4 cell count (aHR = 0.994, 95% CI 0.989–0.998), but not CYP2B6 genotype, were predictive of viral non-suppression. For every doubling of efavirenz concentration there was a 23% decrease in the hazard of non-suppression. A threshold of 0.7 mg/L was found to be the efavirenz mid-dosing concentration that was most predictive of non-suppression. Mid-dosing efavirenz concentrations are predictive of viral non-suppression, but the currently recommended lower therapeutic limit (1 mg/L) is higher than our finding. Knowledge of CYP2B6 metaboliser genotype is not required for prediction of virological outcomes.

Presence of Lamivudine or Emtricitabine Is Associated with Reduced Emergence of Nonnucleoside Reverse Transcriptase Inhibitor Mutations in an Efavirenz-Based Intermittent Antiretroviral Treatment Regimen

Efavirenz concentrations were measured in 21 patients during an interruption cycle of the ANRS 106 Window trial. The median efavirenz concentrations in the patients 12 h, 3 days, and 7 days after discontinuation of the drug were 1,962 ng/ml, 416 ng/ml, and 112 ng/ml, respectively. The half-life ranged from 27 to 136 h. No relationship between efavirenz exposure and detection of nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations was demonstrated. Patients who were treated by a lamivudine- or emtricitabine-based regimen had a lower risk of NNRTI mutation selection.

Efavirenz concentrations in CSF exceed IC50 for wild-type HIV

HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF. CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF). Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145 ng/mL in plasma (IQR 1384-4423) and 13.9 ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026-0.0076; n = 69). The CSF/IC(50) ratio was 26 (IQR 8-41) using the published IC(50) for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC(50) for wild-type HIV. Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC(50) in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.

Long-Term Efavirenz Autoinduction and Its Effect on Plasma Exposure in HIV Patients

We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz autoinduction and disposition among patients with HIV in Tanzania (N = 129). Plasma concentrations (at 16h) of efavirenz and 8-hydroxyefavirenz were quantified at weeks 4 and 16 of therapy. Genotyping was performed to identify cytochrome P450 (CYP) 2B6*6, CYP3A5*3, *6, and *7, and ABCB1-3435C/T genotypes. There were reductions in the median efavirenz concentration (Wilcoxon matched-pair test P < 0.001) and efavirenz/8-hydroxyefavirenz ratio (P < 0.001) by 19 and 32%, respectively, at week 16 as compared with week 4. The proportion of patients with efavirenz concentration <1µg/ml at week 16 was higher by 67, 25, and 5% in CYP2B6*1/*1, *1/*6, and *6/*6 genotypes, respectively. The defined therapeutic range based on observed plasma concentrations is affected by the time point of sampling and the CYP2B6 genotype. The effect of efavirenz autoinduction on reducing plasma exposure continues up to week 16 and predominantly affects CYP2B6 extensive metabolizers. Among CYP2B6 slow metabolizers, the presence of a CYP3A5 genotype allele is associated with greater effects of efavirenz autoinduction on plasma concentrations of the drug. The cumulative induction may influence the long-term antiretroviral therapy outcome, particularly in CYP2B6*1 carriers.

Efavirenz plasma concentrations did not predict cessation of therapy due to neuropsychiatric symptoms in a large randomized trial

To assess whether trial participants who ceased efavirenz (EFV) because of neuropsychiatric events had elevated plasma concentrations, we performed a retrospective case-control study. EFV levels were measured by high-performance liquid chromatography in stored plasma from 35 cases and 75 matched controls. All had taken EFV for at least 4 weeks. Median EFV concentrations did not differ (P = 0.77). Measurement of EFV levels in plasma collected at variable times after the last dose did not predict central nervous system intolerance.

CYP2B6 (c.516G→T) and CYP2A6 (*9B and/or *17) polymorphisms are independent predictors of efavirenz plasma concentrations in HIV‐infected patients

Interindividual variability in efavirenz pharmacokinetics is not entirely explained by the well-recognized CYP2B6 516G-->T single nucleotide polymorphism. The aim of this study was to determine whether polymorphisms in the CYP2A6 gene can be used to enhance the predictability of efavirenz concentrations in human immunodeficiency virus (HIV)-infected native African patients. Mid-dose efavirenz plasma concentrations were determined at 4 and 8 weeks following initiation of antiretroviral therapy in 65 HIV-infected Ghanaian patients. Selected CYP2B6 and CYP2A6 genotypes were determined by commercial 5'-nuclease assays. Relationships between averaged 4- and 8-week mid-dose efavirenz concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches including gene-gene interactions. CYP2B6 c.516G-->T, CYP2B6 c.983T-->C, CYP2A6*9B and CYP2A6*17 allele frequencies were 45, 4, 5 and 12%, respectively. Rifampicin therapy, gender, age and body mass index had no significant influence on efavirenz mid-dose concentrations. Median efavirenz concentrations were more than five times higher (P < 0.001) in patients with CYP2B6 c.516TT genotype compared with GG and GT genotypes. Although none of the CYP2A6 genotypes was associated with altered efavirenz concentrations individually, CYP2A6*9B and/or CYP2A6*17 carriers showed a 1.8 times higher median efavirenz concentration (P= 0.017) compared with noncarriers. Multiple linear regression analysis indicated that the CYP2B6 c.516G-->T polymorphism and CYP2A6 slow-metabolizing variants accounted for as much as 36 and 12% of the total variance in efavirenz concentrations, respectively. Our findings support previous work showing efavirenz oxidation by CYP2A6, and suggest that both CYP2A6 and CYP2B6 genotyping may be useful for predicting efavirenz plasma concentrations.

Effect of rifampicin-based antitubercular therapy and the cytochrome P450 2B6 516G&gt;T polymorphism on efavirenz concentrations in adults in South Africa

Background Rifampicin induces expression of the cytochrome P450 isoenzyme 2B6 (CYP2B6), which metabolizes efavirenz. The CYP2B6 516G&gt;T polymorphism impairs efavirenz metabolism and occurs more commonly in Africans than in Caucasians. We explored the effect of rifampicin-based antitubercular therapy and the 516G&gt;T polymorphism on efavirenz concentrations in HIV- infected patients in South Africa. Methods Between-patient and within-patient comparisons were made of mid-dosing interval efavirenz plasma concentrations in adults on antiretroviral therapy including efavirenz 600 mg daily, with and without antitubercular therapy. Results There were 142 participants (40 were on antitubercular therapy and 102 were controls), the mean weight was 66 kg. Median efavirenz concentration was 2.4 mg/l (interquartile range [IQR] 1.3–3.1) and 1.8 mg/l (IQR 1.4–4.4) in participants on antitubercular therapy and controls, respectively ( P=0.734). Paired efavirenz concentrations during and after antitubercular therapy in 17 participants were also similar ( P=0.113). Genotyping results were 60 (49%) G/G homozygotes, 46 (38%) G/T heterozygotes and 16 (13%) T/T homozygotes. In a multivariate logistic regression model adjusted for sex, weight and concomitant antitubercular therapy, the 516G&gt;T polymorphism was strongly associated with high (&gt;4 mg/l) efavirenz concentrations: odds ratio (OR) 4.4 (95% confidence interval [CI] 1.3–14.9) for G/T versus G/G and 31.1 (95% CI 6.6–146.6) for T/T versus G/G. High efavirenz concentrations were associated with severe sleep disturbance ( P=0.048). Low (&lt;1 mg/l) efavirenz concentrations were associated with virological failure (OR 12.5, 95% CI 2.7–57.3). Conclusions Efavirenz can be used together with rifampicin-based antitubercular therapy without dose adjustment in this population. The 516G&gt;T polymorphism occurred commonly and was associated with high efavirenz concentrations.