Awewura Kwara

CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients

Objective:UDP-glucuronosyltransferase (UGT) 2B7 was recently identified as the main enzyme mediating efavirenz N-glucuronidation. In this study, we determined whether selected UGT2B7 polymorphisms could be used to enhance the prediction of efavirenz plasma concentrations from CYP2B6 and CYP2A6 genotypes. Methods:Mid-dose efavirenz plasma concentrations were determined in 94 HIV-infected Ghanaian patients at 2–8 weeks of antiretroviral therapy. CYP2B6 and CYP2A6 genotypes had been previously reported. UGT2B7 exon 2 single-nucleotide polymorphisms (SNPs) c.735A>G (UGT2B7*1c; rs28365062) and c.802C>T (H268Y; UGT2B7*2; rs7439366) were determined by direct sequencing with UGT2B7*1a defined as the reference allele. Relationships between efavirenz plasma concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches. Results:The mean (±SD) mid-dose efavirenz plasma concentration was 3218 (±3905) ng/ml with coefficient of variation of 121%. Independent predictors of efavirenz concentration included CYP2B6 c.516TT genotype (4030 ng/ml increase; 95% confidence interval 2882–5505 ng/ml, P < 0.001), UGT2B7*1a carrier status (475 ng/ml increase; 95% confidence interval 138–899 ng/ml, P = 0.004) and CYP2A6*9 and/or *17 carrier status (372 ng/ml increase; 95% confidence interval 74–742 ng/ml, P = 0.013). Overall, CYP2B6 c.516TT genotype, UGT2B7*1a carrier status and CYP2A6*9 or *17 carrier status accounted for 45.2, 10.1 and 8.6% of the total variance, respectively. Conclusion:Our findings demonstrate independent effects of CYP2A6 and UGT2B7 genetic variation on efavirenz disposition beyond that of the CYP2B6 polymorphisms. The development and testing of a pharmacogenetic algorithm for estimating the appropriate dose of efavirenz should incorporate genotypic data from both the oxidative and glucuronidation pathways.

Evaluation of the Epidemiologic Utility of Secondary Typing Methods for Differentiation of Mycobacterium tuberculosis Isolates

ABSTRACT Spoligotyping and mycobacterial interspersed repetitive unit-variable-number tandem repeat analysis (MIRU-VNTR) were evaluated for the ability to differentiate 64 Mycobacterium tuberculosis isolates from 10 IS6110-defined clusters. MIRU-VNTR performed slightly better than spoligotyping in reducing the number of clustered isolates and the sizes of the clusters. All epidemiologically related isolates remained clustered by MIRU-VNTR but not by spoligotyping.

Antiretroviral Drug Concentrations and HIV RNA in the Genital Tract of HIV-Infected Women Receiving Long-Term Highly Active Antiretroviral Therapy

OBJECTIVE Our objective was to determine antiretroviral drug concentrations and human immunodeficiency virus (HIV) RNA rebound in cervicovaginal fluid (CVF) in relation to blood plasma (BP) in women receiving suppressive highly active antiretroviral therapy (HAART). METHODS Thirty-four HIV-infected women who had plasma HIV RNA levels < or =80 copies/mL for at least 6 months were enrolled. Sixty-eight paired CVF and BP drug concentrations and HIV RNA levels were determined before and 3-4 h after drug administration. For each woman and antiretroviral drug, the CVF:BP drug concentration ratios before and after drug administration were calculated. The nonparametric Wilcoxon rank sum test was used to determine if these ratios were different from 1.0. RESULTS Lamivudine (administered to 20 patients) and tenofovir (administered to 16) had significantly higher concentrations in CVF than in BP before drug administration, with mean CVF:BP concentration ratios of 3.19 (95% confidence interval, 1.2-8.5) and 5.2 (95% confidence interval, 1.2-22.6), respectively. Efavirenz (administered to 13 patients) and lopinavir (administered to 6) had significantly lower concentrations in CVF, with mean CVF:BP concentration ratios of 0.01 (95% confidence interval, 0.00-0.03) and 0.03 (0.01-0.11), respectively. During the study visit (median time after enrollment, 6 months), BP and CVF detectable HIV RNA levels were observed 7 patients (20.6%) and 1 patient (2.9%), respectively. CONCLUSION Despite lower CVF concentrations of key HAART components, such as efavirenz and lopinavir, virologic rebound was rare. The high concentrations of tenofovir and lamivudine in CVF may have implications for the prevention of sexual transmission during HAART and for pre-exposure or postexposure prophylaxis.

Pharmacokinetics of Efavirenz When Co‐administered With Rifampin in TB/HIV Co‐infected Patients: Pharmacogenetic Effect of CYP2B6 Variation

The goal of this study was to determine the effect of CYP2B6 genetic variation on the steady‐state pharmacokinetics of efavirenz (600 mg/d) in TB/HIV co‐infected patients receiving concomitant rifampin, a potent CYP inducer. In the 26 patients studied, CYP2B6 c.516GG, GT, and TT genotype frequencies were 0.27, 0.50, and 0.23, respectively. Mean plasma efavirenz area under the curve was significantly higher in patients with CYP2B6 c.516TT than in those with GT (107 vs 27.6 μg·h/mL, P < .0001) or GG genotype (107 vs 23.0 μg·h/mL, P < .0001). Apparent oral clearance (CL/F) was significantly lower in patients with CYP2B6 c.516TT than in those with GT genotype (2.1 vs 8.4 mL/min/kg, P < 0.0001) and GG genotype (2.1 vs 9.9 mL/min/kg, P < .0001). No differences in efavirenz exposure or CL/F existed between patients with CYP2B6 c.516GT and GG genotypes. Our results indicate that CYP2B6 c.516TT genotype can be used to identify efavirenz poor metabolizers in patients co‐treated with rifampin.

Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B7*1c is associated with faster zidovudine clearance and glucuronidation.

There are limited data on the pharmacokinetics of generic nucleoside reverse transcriptase inhibitors (NRTIs) in native African populations, in whom they are commonly used. The authors characterized the pharmacokinetics of lamivudine (n = 27), zidovudine (n = 16), and stavudine (n = 11) in human immunodeficiency virus (HIV)/tuberculosis (TB)‐coinfected Ghanaians and evaluated associations between zidovudine metabolism and UDP‐glucuronosyltransferase (UGT) 2B7 polymorphisms. Lamivudine, zidovudine, and stavudine apparent oral clearance (CL/F) values (mean ± SD [% coefficient of variation [CV]) were 7.3 ± 2.8 (39%), 31.9 ± 33.6 (106%), and 16.4 ± 5.8 (35%) mL/min/kg, respectively, whereas half‐life values were 4.2 ± 1.9 (46%), 8.1 ± 7.9 (98%), and 1.5 ± 1.0 (65%) hours, respectively. Zidovudine CL/F was 196% higher (P = .004) in UGT2B7*1c (c.735A>G) carriers versus noncarriers. This was confirmed using human liver bank samples (n = 52), which showed 48% higher (P = .020) zidovudine glucuronidation and 33% higher (P = .015) UGT2B7 protein inUGT2B 7*1c carriers versus noncarriers. In conclusion, generic NRTI pharmacokinetics in HIV/TB‐coinfected Ghanaians are similar to other populations, whereas the UGT2B7*1c polymorphism may explain in part relatively high interindividual variability in zidovudine clearance

Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz.

Objectives. Compare the Plan B levonorgestrel (LNG) area under the concentration- time curve (AUC12) prior to and with efavirenz (EFV). Design. Prospective, open-label, single-arm, equivalence study. Methods. Healthy HIV-negative subjects underwent 12 hr intensive pharmacokinetic (PK) sampling following single dose LNG alone and after 14 days of EFV. Geometric means, Geometric Mean Ratios, and 90% confidence intervals (CI) are reported for PK Parameters. T-tests were utilized. Clinical parameters and liver function tests (LFTs) were assessed. Results. 24 women enrolled and 21 completed the study. With EFV, LNG AUC12 was reduced 56% (95% CI: 49%, 62%) from 42.9 to 17.8 ng∗hr/mL, and maximum concentration (Cmax⁡) was reduced 41% (95% CI: 33%, 50%) from 8.4 to 4.6 ng/mL. LNG was well tolerated with no grade 3 or 4 treatment-related toxicities. Conclusions. EFV significantly reduced LNG exposures. Higher LNG doses may be required with EFV. These results reinforce the importance of effective contraception in women taking EFV.

Paradoxically elevated efavirenz concentrations in HIV/tuberculosis-coinfected patients with CYP2B6 516TT genotype on rifampin-containing antituberculous therapy

Some individuals have higher efavirenz plasma concentrations during rifampin-containing tuberculosis (TB) therapy, contrary to the expected induction effect of rifampin. Among HIV-infected patients without (n = 38) and with TB on rifampin-containing therapy (n = 18), we tested the hypothesis that drug–gene interaction may explain the highly variable drug interactions. Two-way analysis of variance revealed a significant interaction between CYP2B6 516G→T polymorphism and rifampin-containing therapy, suggesting that efavirenz dose adjustment may need to be individualized on the basis of the patients genotype.

Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes

OBJECTIVES Efavirenz is widely prescribed for HIV-1 infection, and CYP2B6 polymorphisms 516G→T and 983T→C define efavirenz slow metabolizer genotypes. To identify genetic predictors of higher plasma efavirenz concentrations beyond these two common functional alleles, we characterized associations with mid-dosing interval efavirenz concentrations in 84 HIV-infected adults, all carrying two copies of these major loss-of-function CYP2B6 alleles. METHODS Study participants had been randomized to efavirenz-containing regimens in prospective clinical trials and had available plasma efavirenz assay data. Analyses focused on secondary metabolism pathway polymorphisms CYP2A6 -48T→G (rs28399433), UGT2B7 735A→G (rs28365062) and UGT2B7 802T→C (rs7439366). Exploratory analyses also considered 196 polymorphisms and 8 copy number variants in 41 drug metabolism/transport genes. Mid-dosing interval efavirenz concentrations at steady-state were obtained ≥8 h but <19 h post-dose. Linear regression was used to test for associations between polymorphisms and log-transformed efavirenz concentrations. RESULTS Increased efavirenz concentrations were associated with CYP2A6 -48T→G in all subjects (P = 3.8 × 10(-4)) and in Black subjects (P = 0.027) and White subjects (P = 0.0011) analysed separately; and with UGT2B7 735 G/G homozygosity in all subjects (P = 0.006) and in Black subjects (P = 0.046) and White subjects (P = 0.062) analysed separately. In a multivariable model, CYP2A6 -48T→G and UGT2B7 735 G/G homozygosity remained significant (P < 0.05 for each). No additional polymorphisms or copy number variants were significantly associated with efavirenz concentrations. CONCLUSIONS Among individuals with a CYP2B6 slow metabolizer genotype, CYP2A6 and possibly UGT2B7 polymorphisms contribute to even higher efavirenz concentrations.

Dose adjustment of the non-nucleoside reverse transcriptase inhibitors during concurrent rifampicin-containing tuberculosis therapy: one size does not fit all.

Importance of the field: HIV/tuberculosis (TB) co-infection is common and associated with high mortality. Simultaneous highly active antiretroviral therapy during TB treatment is associated with substantial survival benefit but drug–drug interactions complicate NNRTI dosing. Areas covered in this review: We reviewed the impact of rifampicin-containing TB therapy on the NNRTIs pharmacokinetics and clinical outcome. PubMed database was searched from 1966 to July 2009 using the terms efavirenz, rifampicin, nevirapine, pharmacokinetics, pharmacogenetics, HIV, TB, CYP2B6, CYP3A4 and metabolism. References from identified articles and abstracts from meetings were also reviewed. What the reader will gain: A comprehensive review of the literature on this subject including pharmacokinetic and clinical studies. Most studies were small, observational or underpowered to detect the true effect of rifampicin on NNRTI-based therapy. None of the studies were controlled for genetic factors and there were limited data on children. Take home message: There were insufficient data to make definitive recommendations about dose adjustment of the NNRTIs during rifampin-containing therapy. Current data suggest that the standard dose of efavirenz or nevirapine is adequate in most HIV/TB co-infected adults. However, more research is needed in pediatric populations as well as to define role of drug–gene interactions.

Impact of Immigration on the Molecular Epidemiology of Tuberculosis in Rhode Island

ABSTRACT While foreign-born persons constitute only 11% of the population in the state of Rhode Island, they account for more than 65% of incident tuberculosis (TB) annually. We investigated the molecular-epidemiological differences between foreign-born and U.S.-born TB patients to estimate the degree of recent transmission and identify predictors of clustering. A total of 288 isolates collected from culture-confirmed TB cases in Rhode Island between 1995 and 2004 were fingerprinted by spoligotyping and 12-locus mycobacterial interspersed repetitive units. Of the 288 fingerprinted isolates, 109 (37.8%) belonged to 36 genetic clusters. Our findings demonstrate that U.S.-born patients, Hispanics, Asian/Pacific islanders, and uninsured patients were significantly more likely to be clustered. Recent transmission among the foreign-born population was restricted and occurred mostly locally, within populations originating from the same region. Nevertheless, TB transmission between the foreign-born and U.S.-born population should not be neglected, since 80% of the mixed clusters of foreign- and U.S.-born persons arose from a foreign-born source case. We conclude that timely access to routine screening and treatment for latent TB infection for immigrants is vital for disease elimination in Rhode Island.