Higher Plasma Efavirenz Concentrations Research Articles

Pharmacokinetics of efavirenz in patients on antituberculosis treatment in high human immunodeficiency virus and tuberculosis burden countries: A systematic review.

Efavirenz (EFV) and rifampicin-isoniazid (RH) are cornerstone drugs in human immunodeficiency virus (HIV)-tuberculosis (TB) coinfection treatment but with complex drug interactions, efficacy and safety challenges. We reviewed recent data on EFV and RH interaction in TB/HIV high-burden countries. We conducted a systematic review of studies conducted in the high TB/HIV-burden countries between 1990 and 2016 on EFV pharmacokinetics during RH coadministration in coinfected patients. Two reviewers conducted article screening and data collection. Of 119 records retrieved, 22 were included (two conducted in children), reporting either EFV mid-dose or pre-dose concentrations. In 19 studies, median or mean concentrations of RH range between 1000 and 4000ngml-1 , the so-called therapeutic range. The proportion of patients with subtherapeutic concentration of RH ranged between 3.1 and 72.2%, in 12 studies including one conducted in children. The proportion of patients with supratherapeutic concentration ranged from 19.6 to 48.0% in six adult studies and one child study. Five of eight studies reported virological suppression >80%. The association between any grade hepatic and central nervous system adverse effects with EFV/RH interaction was demonstrated in two and three studies, respectively. The frequency of the CYP2B6 516G>T polymorphism ranged from 10 to 28% and was associated with higher plasma EFV concentrations, irrespective of ethnicity. Anti-TB drug coadministration minimally affect the EFV exposure, efficacy and safety among TB-HIV coinfected African and Asian patients. This supports the current 600mg EFV dosing when coadministered with anti-TB drugs.

PREVALENCE AND RISK FACTORS FOR EFAVIRENZ-BASED ANTIRETROVIRAL TREATMENT-ASSOCIATED SEVERE VITAMIN D DEFICIENCY: A PROSPECTIVE COHORT STUDY

BackgroundInitiation of efavirenz-based combination antiretroviral therapy (cART) is associated with Vitamin D deficiency, but the risk factors for cART-induced severe vitamin D deficiency (SVDD) and the impact of anti-tuberculosis (TB)...

Prevalence and risk factors for efavirenz-based antiretroviral treatment-associated severe vitamin D deficiency: A prospective cohort study.

Initiation of efavirenz-based combination antiretroviral therapy (cART) is associated with Vitamin D deficiency, but the risk factors including efavirenz pharmacokinetics for cART-induced severe vitamin D deficiency (SVDD) and the impact of anti-tuberculosis (TB) cotreatment are not explored. We investigated the prevalence of SVDD in HIV and TB-HIV coinfected patients and associated risk factors for treatment-induced SVDD.Treatment-naïve Ethiopian HIV patients with (n = 102) or without (n = 89) TB co-infection were enrolled prospectively and received efavirenz-based cART. In TB-HIV coinfected patients, rifampicin-based anti-TB treatment was initiated 4 or 8 weeks before starting cART. Plasma 25-hydroxyvitamin D (25 [OH]D), cholesterol and 4-beta hydroxycholesterol concentrations were measured at baseline, 4th, 16th, and 48th week of cART. Plasma efavirenz concentrations were determined at 4th and 16th weeks of cART.TB-HIV patients had significantly lower plasma 25 (OH)D3 levels than HIV-only patients at baseline. TB co-infection, low Karnofsky score, high viral load, and high CYP3A activity as measured by plasma 4β-hydroxycholesterol/cholesterol ratios were significant predictors of low 25 (OH)D3 levels at baseline. In HIV-only patients, initiation of efavirenz-based cART increased the prevalence of SVVD from 27% at baseline to 76%, 79%, and 43% at 4th, 16th, and 48th weeks of cART, respectively. The median 25 (OH)D3 levels declined from baseline by −40%, −50%, and −14% at 4th, 16th, and 48th weeks of cART, respectively.In TB-HIV patients, previous anti-TB therapy had no influence on 25 (OH)D3 levels, but the initiation of efavirenz-based cART increased the prevalence of SVDD from 57% at baseline to 70% and 72% at the 4th and 16th weeks of cART, respectively. Median plasma 25 (OH)D3 declined from baseline by −17% and −21% at week 4 and 16 of cART, respectively.Our results indicate low plasma cholesterol, high CYP3A activity, and high plasma efavirenz concentrations as significant predictors of early efavirenz-based cART-induced vitamin D deficiency. Low plasma 25 (OH)D3 level at baseline is associated with TB co-infection and HIV diseases progression. Initiation of efavirenz-based cART is associated with high incidence of SVDD, whereas rifampicin based anti-TB therapy co-treatment has no significant effect. Supplementary vitamin D during cART initiation may be beneficial for HIV patients regardless of TB coinfection.

Therapeutic Drug Monitoring and Pharmacogenetic Study of HIV-Infected Ethnic Chinese Receiving Efavirenz-Containing Antiretroviral Therapy with or without Rifampicin-Based Anti-Tuberculous Therapy

ObjectivesPlasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese.MethodsHIV-infected patients with or without TB who had received combination antiretroviral therapy containing efavirenz (600 mg daily) for two weeks or greater were enrolled for determinations of CYP2B6 G516T polymorphism and plasma efavirenz concentrations with the use of polymerase-chain-reaction restriction fragment-length polymorphism and high-performance liquid chromatography, respectively.ResultsFrom October 2009 to August 2012, 171 HIV-infected patients, including 18 with TB, were enrolled 113 (66.1%) with CYP2B6 G516G, 55 (32.2%) GT, and 3 (1.8%) TT genotype. Patients receiving rifampicin had a significantly lower median plasma efavirenz concentration than the control group (2.16 vs 2.92 mg/L, P = 0.003); however, all patients achieved target plasma concentration (>1 mg/L). Patients with GT or TT genotype had a significantly higher plasma concentration than those with GG genotype (2.50 vs 3.47 mg/L for GT genotype and 8.78 mg/L for TT genotype, P<0.001). Plasma efavirenz concentration >4 mg/L was noted in 38 (22.2%) patients, which was associated with a lower weight (per 10-kg increase, odds ratio, 0.52; 95% confidence interval, 0.33–0.83) and GT or TT genotype (odds ratio, 4.35; 95% confidence interval, 1.97–9.59) in multivariate analysis.ConclusionsDespite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB who receive efavirenz 600 mg daily. Carriage of CYP2B6 516 GT and TT genotypes and a lower weight are associated with higher plasma efavirenz concentrations.

Pharmacogenetic markers of CYP2B6 associated with efavirenz plasma concentrations in HIV‐1 infected Thai adults

To investigate the frequency of CYP2B6 polymorphisms and the influence of haplotype structure on plasma efavirenz concentrations in Thai adults with HIV-1 infection. Genotyping of nine single nucleotide polymorphisms (SNPs, c.64C>T, c.499C>G, c.516G>T, c.785A>G, c.1375A>G, c.1459C>T, g.3003T>C, g.18492C>T and g.21563C>T) of CYP2B6 were performed using real-time PCR-based allelic discrimination on blood samples from 52 HIV-infected adults who had received an efavirenz-based regimen. Plasma efavirenz concentrations were measured by high performance liquid chromatography. The minor allele frequencies for c.64C>T, c.516G>T, c.785A>G, g.3003C>T, g.18492T>C and g.21563C>T were 0.087, 0.365, 0.413, 0.308 and 0.356, respectively. However, no variant alleles were identified for three SNPs (c.499 C>G, c.1375 A>G and c.1459 C>T). Efavirenz plasma concentrations were significantly associated with c.516G>T (P= 0.0095), c.785A>G (P= 0.0017), g.21563C>T (P= 0.0036) and g.18492C>T (P= 0.0011). The composite CYP2B6 of three SNPs (c.516G ≥ T, c.785A ≥ G and g.21563C ≥ T) genotypes were significantly associated with higher efavirenz concentrations. Our data indicate that the GAC-CYP2B6 haplotype is associated with higher plasma efavirenz concentrations in HIV-infected Thai adults.

CYP2B6 Polymorphism and Nonnucleoside Reverse Transcriptase Inhibitor Plasma Concentrations in Chinese HIV-Infected Patients

The purpose of this study was to investigate the frequency of CYP2B6 polymorphisms and their influence on plasma concentrations of efavirenz and nevirapine in HIV-infected Chinese patients. After written informed consent, 159 patients were enrolled at Shanghai Public Health Clinical Center. Genotyping for 516 G>T, 785 A>G, 983 T>C, and 1459 T>C polymorphisms in CYP2B6, together with CYP3A4 -392 A>G, CYP3A5 6986 A>G, and ABCB1 (2677 G>T/A, 3435 C>T), were performed. Plasma efavirenz and nevirapine concentrations of 120 patients at steady state were assessed by high-performance liquid chromatography-mass spectrometry. The minor allele frequency for CYP2B6 516 G>T, 785 A>G, 983 T>C, and 1459 T>C was 0.16, 0.24, 0, and 0, respectively; and 0.07, 0.32, 0.15, and 0.35 for CYP3A4 -392 A>G, CYP3A5 6986 A>G, ABCB1 2677 G>T/A, and ABCB1 3435 C>T, respectively. Univariate analysis indicated associations between 516 G>T (P < 0.01) with efavirenz but not nevirapine plasma concentrations. None of other genetic variants was associated with plasma efavirenz or nevirapine concentrations. Although CYP2B6 516 G>T was associated with high plasma efavirenz concentrations, such an association was not evident with nevirapine in this Chinese patient population. CYP3A4 -392 A>G, CYP3A5 6986 A>G, and ABCB1 (2677 G>T/A, 3435 C>T) had no significant impact on plasma efavirenz or nevirapine concentrations.

Successful Use of Reduced‐Dose Efavirenz in a Patient with Human Immunodeficiency Virus Infection: Case Report and Review of the Literature

Efavirenz, a nonnucleoside reverse transcriptase inhibitor, is a highly effective and widely prescribed antiretroviral agent. It is recommended as first-line treatment of human immunodeficiency virus (HIV) infection. The standard dose of efavirenz is 600 mg/day; however, adverse central nervous system effects limit its use. Few data citing use of efavirenz at lower doses have been published. We describe a 35-year-old man with HIV infection whose virologic suppression was maintained after 18 months of treatment with efavirenz 400 mg/day. Genetic testing for cytochrome P450 (CYP) 2B6 showed that the patient was a heterozygous variant; patients with this polymorphism tend to have higher plasma efavirenz concentrations and slower plasma efavirenz clearance (prolonged elimination half-lives). Therapeutic drug monitoring also supported the dose reduction in this patient. Even with the 400-mg dose, the patient's plasma trough concentrations exceeded the upper limit of the therapeutic range. However, as he remained completely asymptomatic with this dose, no further dose reduction was necessary. This case report provides evidence that reduced efavirenz doses may be effective in the treatment of HIV infection. In addition, this case demonstrates that pharmacogenetic and pharmacokinetic testing combined with therapeutic drug monitoring may be used to guide reduced-dose, efavirenz-based therapy.

Successful Efavirenz Dose Reduction in HIV Type 1-Infected Individuals with Cytochrome P450 2B6 *6 and *26

Efavirenz (EFV) is metabolized primarily by cytochrome P450 2B6 (CYP2B6), and high plasma concentrations of the drug are associated with a G-->T polymorphism at position 516 (516G-->T) of CYP2B6 and frequent central nervous system (CNS)-related side effects. Here, we tested the feasibility of genotype-based dose reduction of EFV. CYP2B6 genotypes were determined in 456 human immunodeficiency virus type 1 (HIV-1)-infected patients who were receiving EFV treatment or were scheduled to receive EFV-containing treatment. EFV dose was reduced in CYP2B6 516G-->T carriers who had high plasma EFV concentrations while receiving the standard dosage (600 mg). EFV-naive homozygous CYP2B6 516G-->T carriers were treated with low-dose EFV. In both groups, the dose was further reduced when plasma EFV concentration remained high. CYP2B6 516G-->T was identified in the *6 allele (found in 17.9% of our subjects) and a novel allele, *26 (found in 1.3% of our patients). All EFV-treated CYP2B6 *6/*6 and *6/*26 carriers had extremely high plasma EFV concentrations (>6000 ng/mL) while receiving the standard dosage. EFV dose was reduced to 400 mg for 11 patients and to 200 mg for 7 patients with persistently suppressed HIV-1 loads. EFV-containing treatment was initiated at 400 mg in 4 CYP2B6 *6/*6 carriers and one *6/*26 carrier. Two of them still had a high plasma EFV concentration while receiving that dose, and the dose was further reduced to 200 mg, with successful HIV-1 suppression. CNS-related symptoms improved with dose reduction in 10 of the 14 patients, although some had not been aware of the symptoms at initial dosage. Genotype-based EFV dose reduction is feasible in CYP2B6 *6/*6 and *6/*26 carriers, which can reduce EFV-associated CNS symptoms.

Studies Disagree on Frequency of Late CNS Side Effects from Efavirenz

High plasma efavirenz concentrations and cytochrome P450 2B6 genotype are risk factors for neuropsychiatric problems during the first few weeks of

Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens

Efavirenz (EFV) is metabolized by cytochrome P450 2B6 ( CYP2B6) in the liver. We analyzed the genotypes of CYP2B6 and their contribution to plasma EFV concentrations in 35 EFV-treated patients in International Medical Center of Japan. The mean plasma EFV concentration of patients with CYP2B6 *6/*6 (Q172H and K262R) (25.4 ± 7.5 μM, ± SD, n=2) was significantly higher than that of patients with genotypes *6 heterozygote (9.9 ± 3.3 μM, n=10) or without alleles *6 (8.0 ± 2.6 μM, n=23) ( p<0.0001). To confirm our result, we further analyzed nine patients (three with high EFV concentrations and arbitrarily selected six with normal EFV concentrations) treated in Osaka National Hospital, and it resulted that the only three patients with the high concentrations were the *6/*6 holder. EFV dose could be decreased in those patients harboring the genotype to reduce toxicity with compromising potency, representing the first step of the Tailor-Made therapy of HIV-1 infection.