CYP2B6 516G Research Articles

Pharmacogenetics of Efavirenz Exposure in Cervicovaginal Fluid during Pregnancy and Postpartum.

In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy. Women receiving efavirenz-containing antiretroviral therapy were recruited from two hospitals in Nigeria during 2017-2020. Sparse CVF and plasma samples were obtained during pregnancy to assess the possible association between drug concentration and CYP2B6 polymorphisms (stage I). Participants were stratified into three CYP2B6 516G>T (rs3745274) genotype groups and re-enrolled for intensive pharmacokinetic sampling (stage II). Overall, 159 women (142 pregnant and 12 postpartum) contributed samples in stage I (88 CVF, 81 plasma and 73 paired). CYP2B6 516G>T (rs3745274) remained independently associated with log10 efavirenz CVF concentration during pregnancy after adjusting for plasma concentration, with β (Log10 efavirenz concentration, 95%CI) of 0.204 (0.027, 0.382), P = 0.025). Median (IQR) efavirenz C min in CVF during pregnancy (n = 12) vs. postpartum (n = 12) was 243 ng/mL (168-402) vs. 447 ng/mL (159-974), C max was 1,031 ng/mL (595-1,771) vs. 1,618 ng/mL (675-2,695), and AUC0-24h was 16,465 ng.h/mL (9,356-30,417) vs. 30,715 ng.h/mL (10,980-43,714). CVF-to-plasma AUC ratio was 0.36 during pregnancy and 0.46 postpartum. Upon stratification, efavirenz clearance during pregnancy was 57.9% higher than postpartum in patients with the CYP2B6 516GT genotype; the AUC0-24h and C max were 33.8% and 8.6% lower, respectively. Efavirenz C min in CVF exceeded the protein binding-adjusted IC90 (PBIC90) of 126 ng/mL during pregnancy and postpartum. Efavirenz is well distributed into the CVF; both pregnancy and CYP2B6 polymorphisms affect the extent of exposure.

Cytochrome P450 2B6 6 distribution among patients living with HIV in Burkina Faso

The function of cytochrome P450 (CYP) enzymes, one of the major catalysts in drug metabolism, is significantly influenced by genetic polymorphisms leading to substantial inter-individual variability in drug response and/ or adverse reactions activity. The aim of this study was to determine the frequency of the CYP2B6 516G>T allele in patients living with HIV receiving treatment at the Medical Center of Camp General Aboubacar Sangoule Lamizana for whom the treatment was changed after the initiation of treatment because of the appearance of side effects. 155 HIV-positive patients were enrolled. Genomic Deoxyribonucleic acid (DNA) extraction from blood was performed using the GenJET® Genomic DNA according to the manufacturer’s instructions. Genotyping for the cytochrome P450 variant alleles was performed using predesigned primers. The amplification was carried out by Polymerase Chain Reaction (PCR), while the differentiation between the alleles was carried out after digestion with restriction enzymes by electrophoresis. The results obtained showed. Among these patients, 61 changed treatments during their follow-up. The majority of the 61 patients, 32 patients, received an initial treatment regimen based on the AZT (3'-Azido-3'-Deoxythymidine)/3TC (Lamivudine)/ NVP(Nevirapine) combination, followed by 18 patients for the TDF (tenofovir)/3TC (lamivudine)/ EFV(Efavirenz) regimens. Currently, the majority of patients, 48 patients, have benefited from a therapeutic regimen based on the TDF (tenofovir)/3TC (lamivudine) /DTG(Dolutegravir) combination, followed by 11 patients for the TDF (tenofovir)/3TC (lamivudine)/EFV(Efavirenz) regimens. The distribution of the major allele CYP2B6*T was 68%, and the minor CYP2B6*G allele was 32%. Heterozygote (GT genotype) and Homozygous mutants (TT genotype) and Heterozygote were 31% and 52,5%. Studies could be continued to set up cytochrome mutation detection kits to anticipate the onset of side effects and adapt treatments.

Cytochrome P450 2B6 6 distribution among Burkinabè population

Mutations affect the genes that encode certain cytochromes P450 (CYP450) isoenzymes that are responsible for metabolism of drugs. The aim of this study was to determine the frequency of CYP2B6 (516G>T) SNP in the Burkinabè population. Genomic DNA extraction from blood was performed by GenJET® Genomic DNA according to the manufacturer’s instructions. Genotyping for the cytochrome P450 variant alleles was performed using predesigned primers. The amplification was carried out by PCR while the differentiation between the alleles was carried out after digestion with restriction enzymes by electrophoresis. The CYP2B6 c.516G>T was successfully analyzed in 92,38% (291/315) of the study participants. Among the investigated individuals, the distribution of the major allele CYP2B6*G was 56% and the minor CYP2B6*T allele was 44%. The results obtained showed a prevalence of 56% for the G allele and 44% for the T allele. This was distributed as 31% for the GG genotype (reduced dosage required), 51% for the GT genotype (normal dosage range), and 18% for the TT genotype (high drug toxicity). The presence of the rapid and poor metabolizer phenotypes in the studied sample shows the need for additional studies to better assess their impact on Burkinabe people.

Influence of CYP2B6 Genotype on Methadone Dosage in Patients from the Methadone Maintenance Treatment (MMT) Program in Pereira, Colombia.

Methadone treatment reduces the use of heroin and withdrawal symptoms; however, methadone is an expensive medication with a narrow safety margin. We compared the retention rates, persistence of heroin use, and quality of life of a group of patients undergoing conventional Methadone Maintenance Treatment (MMT) with a group for whom the CYP2B6 516G>T polymorphism was used in addition to the MMT to calculate the required methadone dose. Over 12 weeks, the retention rate, heroin usage, and quality of life of patients under conventional treatment (n = 34) were compared with those of patients for whom we used genetic markers to calculate methadone dosage (n = 38). At the end of the study, 26.4% of patients abandoned the program, and neither demographic nor clinical variables were associated with treatment adherence. Of the remaining patients, 16% of the control group and 8% of patients in the pharmacogenetic group reported heroin use, while both groups showed a 64% reduction in the use of cocaine/crack (no significant differences between the groups were found). Starting in the second week, the methadone dosage was lower among the patients for whom methadone was prescribed based on genotype. Although there were six individuals in the control group and three in the pharmacogenetic group with QTc intervals > 450 ms (a threshold that is considered dangerous), we did not find a relationship between the QTc interval and methadone dosage. There were no differences in the perception of quality of life between the two groups. The results of this pilot study suggest that concerning methadone therapy, the CYP2B6 genotype contributes to reduced effective doses and treatment costs.

Effects of rifampicin, CYP2B6 and ABCB1 polymorphisms on efavirenz plasma concentration in Chinese patients living with HIV and tuberculosis.

Tuberculosis (TB) is the leading opportunistic infection of people living with human immunodeficiency virus (HIV; PLWH). Cytochrome P450 (CYP) 2B6 and ATP-binding cassette sub-family B member 1 (ABCB1) are involved in the metabolism and transportation of efavirenz. The study was aimed to investigate the effects of rifampicin, CYP2B6 and ABCB1 polymorphisms on efavirenz exposure in Chinese PLWH co-infected with TB. PLWH were screened according to inclusion and exclusion criteria and divided into HIV group and HIV/TB group. Efavirenz plasma concentration (C0) was determined, dose-adjusted concentration (C0/D) was calculated, and genotypes of CYP2B6 516G>T, 785A>G, and ABCB1 2677G>T, 3435C>T were analyzed. 252 PLWH were enrolled, including 75 co-infected with TB and concomitant with rifampicin. Efavirenz C0 and C0/D were both higher in HIV group (1.94μg/mL, 0.2007 (μg/ml)/(mg/kg/d)) compared with HIV/TB group (1.52μg/mL, 0.1557 (μg/ml)/(mg/kg/d)) (p = .001). Efavirenz C0/D was significantly higher in patients with variant genotypes of CYP2B6 516G>T and 785A>G (p<.001), and was significantly lower in HIV/TB group compared with HIV group among patients with CYP2B6 516GG, TT, and 785 AA, AG genotypes (p < .05). Efavirenz exposure is reduced by co-administration with rifampicin, and related to genetic polymorphisms of CYP2B6.

Plasma levels of efavirenz and frequency of the CYP2B6 516G>T polymorphism in people living with HIV-1 in Mexico.

Efavirenz (EFV) is a widely used antiretroviral, due to its safety, efficacy, and low cost. However, plasma concentrations have been related with an increased risk of virological failure and the appearance of serious adverse reactions. EFV is metabolized by Cytochrome P450, the main isoenzyme involved is CYP2B6 and the most relevant genetic polymorphisms found in several populations has been the CYP2B6 516G> T. The aim of this study was to identify the frequency of the CYP2B6 516G>T polymorphism and its effect on the plasma concentration of efavirenz (EFV) in a group of people living with HIV (PLWH) and undergoing EFV treatment in Morelos, Mexico. Ninety-six PLWH undergoing EFV treatment, at a daily dose of 600 mg orally in combination with other antiretrovirals (ARVs), were included in this study. The CYP2B6 516G>T polymorphism was detected using PCR-RFLP. The plasma concentrations of EFV were evaluated by high-resolution liquid chromatography coupled to a mass-mass detector, using a protein precipitation method. The median plasma EFV concentration was 4.6 μg/mL (IQR = 4.64) and 64.6% of the subjects had concentrations above the therapeutic range. The CYP2B6 516G>T genotype findings were as follows: 46.9% of the population presented the wild-type genotype (GG), while 45.8 % and 7.3 % showed the heterozygote (GT) and the polymorphic homozygote (TT) genotype, respectively. The homozygote G had the lowest plasma concentrations of EFV (median = 4.1 μg/mL and IQR = 1.7 μg/mL), followed by those with the GT genotype (median = 5.1 μg/mL and IQR = 3.0 μg/mL). Participants with the homozygous T genotype had the highest EFV concentrations (median = 9.7 μg/mL and IQR = 5.8 μg/mL). In conclusion, the CYP2B6 516G>T polymorphism was associated with plasma levels of EFV in PLWH undergoing ARV treatment. EFV plasma concentrations at 600mg doses were outside the therapeutic range in most subjects.

Associations between efavirenz concentrations, pharmacogenetics and neurocognitive performance in people living with HIV in Nigeria.

Objective:Efavirenz (EFV) use is associated with neuropsychiatric side effects, which may include poor neurocognitive performance. We evaluated single nucleotide polymorphisms in genes that contribute to EFV pharmacokinetics and examined them in association with EFV concentrations in plasma and hair, as well as neurocognitive performance.Design:Cross-sectional study in which adults with HIV receiving 600-mg EFV for at least 2 months were recruited and paired hair and dried blood spots (DBS) samples collected.Methods:Participants (N = 93, 70.3% female) were genotyped for seven single nucleotide polymorphisms in CYP2B6, NRII3 and ABCB1 using DBS. EFV was quantified in DBS and hair using validated liquid-chromatography–tandem-mass-spectrometry methods, with plasma EFV concentrations derived from DBS levels. Participants were also administered a neurocognitive battery of 10 tests (seven domains) that assessed total neurocognitive functioning.Results:Strong correlation (r = 0.66, P < 0.001) was observed between plasma and hair EFV concentrations. The median (interquartile range) hair EFV concentration was 6.85 ng/mg (4.56–10.93). CYP2B6 516G>T, (P < 0.001) and CYP2B6 983T>C (P = 0.001) were each associated with hair EFV concentrations. Similarly, 516G>T (P < 0.001) and 983T>C (P = 0.009) were significantly associated with plasma EFV concentration. No other genetic associations were observed. Contrary to other studies, total neurocognitive performance was significantly associated with plasma EFV concentrations (r = 0.23, P = 0.043) and 983T>C genotype (r = 0.38, P < 0.0005).Conclusion:This study demonstrated approximately three-fold and two-fold higher EFV plasma and hair concentrations, respectively, among CYP2B6 516TT compared with 516GG. Higher EFV concentrations were associated with better neurocognitive performance, requiring further study to elucidate the relationships between adherence, adverse effects and outcomes.

Impact of Efavirenz Mid-dose Plasma Concentration on Long-Term Weight Change Among Virologically Suppressed People Living With HIV

Pharmacogenetic studies have shown that slow and intermediate metabolizers of efavirenz (EFV) gained less weight compared to extensive metabolizers. It is hypothesized that increased EFV exposure suppresses weight gain. We investigated the effect of EFV mid-dose plasma concentration (C12) on long-term weight change among virologically suppressed people living with HIV (PLWH). Participants in a prospective EFV pharmacokinetic study were included if they had been taking EFV-containing combination antiretroviral therapy for more than 240 weeks and had three or more weight measurements. The weight changes and time to ≥5% of weight gain over 192 weeks were compared between PLWH with higher and those with lower EFV C12 (using mean population C12 as the cutoff). EFV C12 and CYP2B6 516G>T polymorphism were examined in generalized estimating equations (GEE) and in a Cox proportional hazards model for associations with weight gain, after adjustments for age, sex, companion antiretroviral agent, CD4 lymphocyte count, and plasma HIV RNA. One-hundred and eighteen PLWH were included. PLWH with higher EFV C12 had less mean weight gain compared to those with lower C12 after 192 weeks (-0.09 kg vs +1.58 kg, p = 0.033). PLWH with higher C12 were less likely to gain ≥5% weight in Kaplan-Meier analysis (p = 0.0003). In both GEE and Cox proportional hazards models, a higher EFV C12 was associated with less weight gain, while CYP2B6 516G>T was not, after adjustments made for confounding factors. Our findings support that increased EFV exposure was associated with less weight gain.

Association of CYP2B6 Genetic Variation with Efavirenz and Nevirapine Drug Resistance in HIV-1 Patients from Botswana.

PurposeCYP2B6 liver enzyme metabolizes the two non-nucleoside reverse transcriptase inhibitors Efavirenz (EFV) and Nevirapine (NVP) used in the antiretroviral therapy (ART) regimens for HIV-infected individuals. Polymorphisms of the CYP2B6 gene influence drug levels in plasma and possibly virological outcomes. The aim of this study was to explore the potential impact of CYP2B6 genotype and haplotype variation on the risk of developing EFV/NVP drug resistance mutations (DRMs) in HIV-1 patients receiving EFV-/NVP-containing regimens in Botswana.Patients and MethodsParticipants were a sub-sample of a larger study (Tshepo study) conducted in Gaborone, Botswana, among HIV-infected individuals taking EFV/NVP containing ART. Study samples were retrieved and assigned to cases (with DRMs) and controls (without DRMs). Four single-nucleotide polymorphisms (SNPs) in the CYP2B6 gene (−82T>C; 516G>T; 785A>G; 983T>C) were genotyped, the haplotypes reconstructed, and the metabolic score assigned. The possible association between drug resistance and several independent factors (baseline characteristics and CYP2B6 genotypes) was assessed by Binary Logistic Regression (BLR) analysis. EFV/NVP resistance status and CYP2B6 haplotypes were also analyzed using Z-test, chi-square and Fisher’s exact test statistics.ResultsTwo hundred and twenty-seven samples were analysed (40 with DRMs, 187 without DRMs). BLR analysis showed an association between EFV/NVP resistance and CYP2B6 516G allele (OR: 2.26; 95% CI: 1.27–4.01; P=0.005). Moreover, haplotype analysis revealed that the proportion of EFV/NVP-resistant infections was higher among CYP2B6 fast than extensive/slow metabolizers (30.8% vs 16.8%; P=0.035), with the 516G allele more represented in the haplotypes of fast than extensive/slow metabolizers (100.0% vs 53.8%; P<0.001).ConclusionWe demonstrated that the CYP2B6 516G allele, and even more when combined in fast metabolic haplotypes, is associated with the presence of EFV/NVP resistance, strengthening the need to assess the CYP2B6 genetic profiles in HIV-infected patients in order to improve the virologic outcomes of NNRTI containing ART.

1020. Higher efavirenz mid-dose plasma concentration is associated with less weight gain among virologically suppressed people living with HIV

BackgroundRecently, an association between CYP2B6 516 G > T polymorphism and weight change was observed among African people living with HIV (PLWH) who were started on efavirenz(EFV)-based antiretroviral therapy (ART). We aimed to investigate the effect of EFV mid-dose plasma concentration on weight change among Taiwanese PLWH.MethodsThe medical records of adult PLWH who were taking EFV-containing ART and had been enrolled in a EFV therapeutic drug monitoring study between Oct 2009 and May 2014 were accessed. EFV mid-dose plasma concentration (C12) was determined in the previous study and those with serial weight measurements within 48 weeks around the time of EFV C12 measurement were included in the present study. The weight change in the 48 weeks and its associations with mid-dose EFV concentrations and CYP2B6 516 G > T polymorphism were examined by general estimating equations (GEE) after adjusting for age, baseline HIV viremia, baseline weight, and the companion backbone antiretroviral agents.ResultsOne-hundred and fifteen predominantly male (94.8%) PLWH were included in this study (Table 1). The mean CD4 lymphocyte count was 542 cells/μL at the beginning of the observation and 94.8% achieved HIV viral suppression. Forty-four (38.3%) patients had non-wildtype CYP2B6 516 G > T polymorphism. On average, the included PLWH gained 0.8 kilogram at 48 weeks and the weight change did not differ among those with wildtype and non-wildtype CYP2B6 516 G > T(Figure 1). In the GEE models, CYP2B6 516 G > T polymorphism was not associated with weight change (p=0.81), instead, higher EFV C12 was found to be independently associated with less weight gain (p=0.045).Table 1. Baseline characteristics. Figure 1. The absolute weight (A) and weight change from baseline (B) among patients with wildtype and non-wildtype CYP2B6 516G>T polymorphism. ConclusionOur findings support that increased EFV exposure may have a negative effect on weight gain.Disclosures Chien-Ching Hung, MD,PHD, Abbvie (Advisor or Review Panel member, Speaker’s Bureau)Bristol-Myers Squibb (Speaker’s Bureau)Gilead Sciences (Advisor or Review Panel member, Speaker’s Bureau)Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)ViiV (Grant/Research Support, Advisor or Review Panel member, Speaker’s Bureau)

Pharmacogenomics and pharmacokinetics of efavirenz 400or 600mg in 184 treatment-naive HIV-infected patients in China.

Background: The pharmacogenomics and pharmacokinetics/pharmacodynamics of 400mg efavirenz have rarely been reported. Materials & methods: A total of 184 treatment-naive HIV-infected patients were randomly assigned (1:1) to receive a lower dose (tenofovir disoproxil 200mg, efavirenz 400mg andlamivudine) or a standard dose regimen. Relationships between pharmacogenomics and efavirenz pharmacokinetics/pharmacodynamics were explored at 48weeks. Results: There was no relationship between pharmacogenomics and adverse reactions of the central nervous system and antiretoviral efficacy. CYP2B6 516G>T, 785A>G, 18492C>T and ABCB1 3435C>T T/C were associated with higher efavirenz plasma levels in the standard but not the lower dose group. No relationship was found between pharmacogenomics and antiretoviral efficacy. Patients who were<60kg had higher efavirenz concentration compared with those with weight ≥60kg when using 600 mgefavirenz, this was not observed with400mg efavirenz. Conclusion: The effect of pharmacogenomics and body weight on the efavirenz concentration was significant in the 600 mggroupbut not in the 400mg group.

Dosage Optimization of Efavirenz Based on a Population Pharmacokinetic–Pharmacogenetic Model of HIV-infected Patients in Thailand

PurposeEfavirenz exhibits high interindividual variability in plasma concentrations, leading to unpredictable efficacy and toxicity. Polymorphism of CYP2B6 516G > T has been found to predominantly contribute to efavirenz variability. However, dosage recommendations incorporating CYP2B6 516G > T polymorphism have not been investigated in the Thai population. This study aimed to develop a population model of the pharmacokinetic properties of efavirenz, and to investigate the impact of patients' characteristics and CYP2B6 516G > T polymorphism on the pharmacokinetic properties of efavirenz. Model-based simulations were performed to provide genotype-based dosage optimization in a Thai population. MethodsPlasma efavirenz concentrations measured at 12 h post-dose in 360 Thai HIV-infected patients with and without tuberculosis were analyzed by the nonlinear mixed-effects modeling approach. A 1-compartment model with first-order absorption and elimination was used for describing the pharmacokinetic properties of efavirenz. FindingsThe allele frequency of CYP2B6 516G > T was 34.17%. The efavirenz oral clearance were 11.9, 8.0, and 2.8 L/h in patients weighing 57 kg and having the CYP2B6 516 GG, 516 GT, and 516 TT genotypes, respectively. The use of rifampicin increased efavirenz oral clearance by 28%. The results from the simulations suggest that efavirenz dosages of 400, 300, and 100 mg once daily in Thai HIV mono-infected patients, and 800, 600, and 200 mg once daily in HIV/tuberculosis co-infected patients carrying CYP2B6 516 GG, 516 GT, and 516 TT, respectively. ImplicationThe results from this study provide a rationale for efavirenz dose adjustment based on CYP2B6 516G > T polymorphism in Thai HIV-infected patients, which could help to improve treatment outcomes in this population. ClinicalTrials.gov identifier: NCT01138267.

&lt;p&gt;The Effect of &lt;em&gt;UGT1A9&lt;/em&gt;, &lt;em&gt;CYP2B6&lt;/em&gt; and &lt;em&gt;CYP2C9&lt;/em&gt; Genes Polymorphism on Propofol Pharmacokinetics in Children&lt;/p&gt;

PurposeThis study was conducted to determine the effect of UGT1A9 98T>C, CYP2B6 516G>T and CYP2C9 430C>T genetic polymorphisms on the pharmacokinetics of propofol in children of different sexes and ages who undergone total intravenous anesthesia (ТIVA) and deep sedation during diagnostic and therapeutic procedures.Patients and MethodsThe prospective study included 94 children, ASA I-II status, 1 to 17 years of age, who undergone standard anesthetic protocol for TIVA, which implied the continuous use of propofol. Before the administration of propofol, venous blood was sampled to determine the presence of genetic variations in UGT1A9, CYP2B6 and CYP2C9 gene using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). From each patient included in the study blood samples were taken: 10 mins after the induction of anesthesia, immediately before the discontinuation of the propofol infusion, 10 mins after discontinuation of the propofol infusion and 20 mins after discontinuation of the propofol infusion to determine the pharmacokinetics of the drug in the plasma of the subjects The plasma propofol concentration was determined by HPLC analytical technique.ResultsUGT1A9 genotype is an independent predictor of the propofol concentration in children immediately after the end of the continuous infusion and 10 mins afterwards. In the carriers of the polymorphic UGT1A9 C allele, the propofol distribution constant was higher. The carriers of the polymorphic CYP2B6 T allele received a significantly lower overall and initial dose of propofol. Unlike polymorphism of the UGT1A9 gene, the tested CYP2C9 and CYP2B6 gene polymorphisms are not independent predictors of the pharmacokinetics of propofol.ConclusionFurther investigations of UGT1A9, CYP2B6 and CYP2C9 and other genes that participate in propofol metabolism as well as detailed analyses of the general conditions, administered therapies and associated diseases could explain the large interindividual variability of propofol metabolism in children.

Effect of First-Line Antituberculosis Therapy on Nevirapine Pharmacokinetics in Children Younger than Three Years Old.

Nevirapine-based antiretroviral therapy (ART) is one of the limited options in HIV-infected children younger than 3 years old (young children) with tuberculosis (TB) coinfection. To date, there are insufficient data to recommend nevirapine-based therapy during first-line antituberculosis (anti-TB) therapy in young children. We compared nevirapine pharmacokinetics (PK) in HIV-infected young children with and without TB coinfection. In the coinfected group, nevirapine PK was evaluated while on anti-TB therapy and after completing an anti-TB therapy regimen. Of 53 participants, 23 (43%) had TB-HIV coinfection. While the mean difference in nevirapine PK parameters between the two groups was not significant (P > 0.05), 14/23 (61%) of the children with TB-HIV coinfection and 9/30 (30%) with HIV infection had a nevirapine minimum concentration (Cmin) below the proposed target of 3.0 mg/liter (P = 0.03). In multivariate analysis, anti-TB therapy and the CYP2B6 516G>T genotype were joint predictors of nevirapine PK parameters. Differences in nevirapine PK parameters between the two groups were significant in children with CYP2B6 516GG but not the GT or TT genotype. Among 14 TB-HIV-coinfected participants with paired data, the geometric mean Cmin and area under the drug concentration-time curve from time zero to 12 h (AUC0-12) were about 34% lower when patients were taking anti-TB therapy, while the nevirapine apparent oral clearance (CL/F) was about 45% higher. While the induction effect of anti-TB therapy on nevirapine PK in our study was modest, the CYP2B6 genotype-dependent variability in the TB drug regimen effect would complicate any dose adjustment strategy in young children with TB-HIV coinfection. Alternate ART regimens that are more compatible with TB treatment in this age group are needed. (This study has been registered at ClinicalTrials.gov under identifier NCT01699633.).

High efavirenz serum concentrations in TB/HIV-coinfected Ugandan adults with a CYP2B6 516 TT genotype on anti-TB treatment.

To report the efavirenz serum concentrations in TB/HIV-coinfected Ugandan adults on concomitant anti-TB treatment and analyse factors associated with elevated concentrations in this specific population. Serum efavirenz concentrations in TB/HIV-coinfected Ugandan adults on efavirenz-based ART (600 mg daily) were measured onsite at 2, 8, 12 and 24 weeks of concomitant anti-TB treatment, including rifampicin. Genetic analysis was done retrospectively through real-time PCR by allelic discrimination (CYP2B6 516G>T, rs3745274). Univariable and multivariable logistic regression analyses were done to assess factors potentially associated with elevated efavirenz serum concentrations. A total of 166 patients were included in the analysis. The median age was 34 (IQR = 30-40) years, 99 (59.6%) were male, the median CD4 cell count was 195 (IQR = 71-334) cells/mm3 and the median BMI was 19 (IQR = 17.6-21.5) kg/m2. Almost half of all patients (82, 49.4%) had at least one efavirenz serum concentration above the reference range of 4 mg/L. The serum efavirenz concentrations of patients with genotype CYP2B6 516 TT were consistently above 4 mg/L and significantly higher than those of patients with GG/GT genotypes: CYP2B6 516 TT 9.6 mg/L (IQR = 7.3-13.3) versus CYP2B6 516 GT 3.4 mg/L (IQR = 2.1-5.1) and CYP2B6 516 GG 2.6 mg/L (IQR = 1.3-4.0) (Wilcoxon rank-sum test: P < 0.0001). A large proportion of our study participants had at least one efavirenz serum concentration >4 mg/L. The CYP2B6 516 TT genotype was the strongest predictor of high concentration. Physicians should be vigilant that efavirenz serum concentrations may be elevated in patients on concomitant anti-TB treatment and that individualized care is warranted whenever possible.

The Prevalence of CYP2B6 Gene Polymorphisms in Malaria-endemic Population of Timor in East Nusa Tenggara Indonesia.

ObjectivesThe CYP2B6 is one of the most polymorphic CYP genes in humans that has the potential to modify the pharmacological and toxicological responses to clinically important drugs such as antimalarial artemisinin and its derivatives. The aim of the study was to determine the frequency of CYP2B6 polymorphisms in Timor malaria endemic area, East Nusa Tenggara, Indonesia where Artemisin-based Combination Therapy (ACT) has been used to treat uncomplicated malaria.MethodsA total of 109 healthy subjects were participated in this study. CYP2B6*4, *6 and *9 polymorphisms were analyzed using PCR-RFLP to confirm the SNPs prevalence of 516G>T and 785A>G in exon 4 and 5.ResultsThere were 96 subjects included in the analysis. In the exon 4 of CYP2B6 516G>T, the frequency of the T mutation was 37.5% (39/96), and the wildtype 27.1% (26/96). In the exon 5, CYP2B6 785A>G mutant was detected in 29.2% (28/96) of individuals, and the wildtype allele in 35.4% (34/96). The frequency of CYP2B6*9 (516G>T), CYP2B6*4 (785A>G) and CYP2B6*6 (516G>T and 785A>G) were 40.6%, 29.2% and 22.9%, respectively. The prevalence of these CYP2B6 gene polymorphisms in Timorian ethnic were higher than that in Malay, Han Chinese, Indian, and Egyptian populations.ConclusionThe prevalence of these CYP2B6 516G>T and 785A>G polymorphisms in Timorian ethnic is higher than that in other populations. These polymorphisms may affect the metabolism of artemisinin and its derivatives.

Impact of Efavirenz Metabolism on Loss to Care in Older HIV+ Africans.

We conducted a prospective cohort study of 914 treatment-naïve HIV+ adults initiating efavirenz-based antiretroviral treatment at public HIV clinics in Gaborone, Botswana between 2009 and 2013. Older age, defined as age ≥ 50years, was the primary exposure and loss to care at 6months was the primary outcome. Interaction between age and CYP2B6 516G>T and 983T>C polymorphisms, defined as extensive, intermediate, and slow metabolism, was assessed. Neurocognitive toxicity was measured using a symptom questionnaire. Age-stratified logistic regression was performed to identify factors associated with loss to care. Older age was associated with loss to care (OR 1.95, 95% CI 1.30-2.92). Age modified the effect of CYP2B6 genotype on loss to care with older, slow metabolizers at over four-fold higher risk when compared to older, intermediate metabolizers (OR 4.06 95% CI 1.38-11.89); neurocognitive toxicity did not mediate this risk. CYP2B6 metabolism genotype did not increase risk of loss to care in younger participants. Older age was associated with loss to care, especially among those with slow efavirenz metabolism. Understanding the relationship between older age and CYP2B6 genotype will be important to improving outcomes in an aging population initiating efavirenz-based ART in similar settings.

Effect of sex and polymorphisms of CYP2B6 and UGT1A9 on the difference between the target-controlled infusion predicted and measured plasma propofol concentration

IntroductionTo examine whether sex and polymorphisms of cytochrome P450 (CYP) 2B6 and UDP-glucuronosyltransferase (UGT) 1A9 affect the difference between predicted and measured plasma propofol concentration during continuous infusion by target-controlled infusion.ResultsBlood samples of 69 patients (48 men and 21 women) were obtained at 4 h after initial propofol infusion. Percentage performance error (PE) was calculated to assess the difference between measured and predicted propofol concentration. Regression coefficients (β) and 95% confidence intervals (CI) of sex and the polymorphisms of CYP2B6 and UGT1A9 for PE were, separately and mutually, estimated with linear regression. Covariates included age and body mass index in the minimal adjusted model, and additionally included clinical factors (mean blood pressure, heart rate, volume of intravenous fluid, surgical site, surgical position, and pneumoperitoneum) in the full adjusted model. PE was higher in men than in women (28.7% versus 10.5%, p = 0.015). Female sex was inversely associated with PE: the minimal adjusted β = − 8.84 (95% CI, − 16.26 to − 1.43); however, the fully adjusted β with clinical factors became not significant. The average of PE did not differ between polymorphisms of CYP2B6 and UGT1A9, and β of CYP2B6 516G>T polymorphisms mutually adjusted with female sex was not significant. Mean blood pressure, heart rate, and volume of intravenous fluid were independently associated with PE in the full adjusted model.ConclusionsUnder 4 h anesthesia with propofol target-controlled infusion in our population, sex differences appeared to exist in the propofol concentration, which might be largely mediated by clinical factors, such as hemodynamic status.Trial registrationUMIN-CTR UMIN000009015, Registered 1 October 2012

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana.

Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics are dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p=0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after one month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

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.