[Show abstract][Hide abstract] ABSTRACT: Efavirenz is commonly used to treat patients co-infected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with CYP2B6*6/*6 genotype (but not CYP2B6*1/*1 genotype) during coadministration with the commonly used four drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction. In vitro studies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (Ki = 368 μM) and pyrazinamide (Ki = 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (KI = 30 μM; kinact = 0.023 min(-1)) and recombinant CYP2A6 (KI = 15 μM; kinact = 0.024 min(-1)), and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes or CYP2B6*6 genotyped HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.
Antimicrobial Agents and Chemotherapy 05/2014; · 4.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Among individuals with a CYP2B6 slow metabolizer genotype, CYP2A6 and possibly UGT2B7 polymorphisms contribute to even higher efavirenz concentrations.
Journal of Antimicrobial Chemotherapy 04/2014; · 5.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify factors associated with variability in rifampin plasma pharmacokinetics and explore the relationship between rifampin pharmacokinetics and change in efavirenz plasma pharmacokinetics with rifampin coadministration.
In this randomized, cross-over study, 12 healthy volunteers received either efavirenz 600 mg/day or efavirenz 600 mg with rifampin 600 mg/day for 8 days. After a washout period of at least 2 weeks, subjects crossed over to the alternate 8-day regimen. Samples were obtained for pharmacokinetic assessment on day 8 of each study cycle. Drugs concentrations were determined by a validated high-performance liquid chromatography. Pharmacokinetic parameters were calculated using noncompartmental analysis. Multivariate analysis was used to examine factors associated with rifampin pharmacokinetics. Spearman correlation analysis was used to investigate relationship between rifampin pharmacokinetics and change in efavirenz plasma pharmacokinetics with rifampin coadministration.
Of 11 evaluable subjects, the median interquartile range, rifampin peak concentration (Cmax) , area under the concentration-time curve (AUC0-24 hour ), and weight-normalized clearance were 8.9 (7.3-13.8) μg/ml, 48.8 (29.6-67.4) μg·h/ml, and 0.19 (0.11-0.29) L/h/kg, respectively. Solute carrier organic anion transporter family member 1B1 (SLCO1B1) c.388A→G and SLCO1B1 c.463C→A polymorphisms jointly had significant effect on rifampin Cmax (R(2) = 0.75). Male sex and SLCO1B1 c.463C→A polymorphism together influenced rifampin AUC0-24 hour (R(2) = 0.52) and weight-normalized clearance (R(2) = 0.65). All four volunteers with rifampin Cmax less than 8 μg/ml (lower end of the normal range) had c.463CA genotype. Rifampin Cmax and AUC0-24 hour had no significant relationship with the efavirenz AUC0-24 hour ratio or weight-normalized clearance ratio in the presence versus absence of rifampin (p>0.05).
Men with the SLCO1B1c.463CA genotype are at increased risk of lower rifampin plasma exposure. However, plasma rifampin concentrations did not correlate with the extent of induction of efavirenz clearance by rifampin during coadministration.
[Show abstract][Hide abstract] ABSTRACT: Compare the Plan B levonorgestrel (LNG) area under the concentration- time curve (AUC(12)) prior to and with efavirenz (EFV). Design. Prospective, open-label, single-arm, equivalence study.
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.
24 women enrolled and 21 completed the study. With EFV, LNG AUC(12) was reduced 56% (95% CI: 49%, 62%) from 42.9 to 17.8 ng∗hr/mL, and maximum concentration (C(max)) 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.
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.
Infectious Diseases in Obstetrics and Gynecology 01/2012; 2012:137192.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to investigate risk factors associated with tuberculosis (TB) transmission that was caused by Mycobacterium tuberculosis strain MS0006 from 2004 to 2009 in Hinds County, Mississippi.
DNA fingerprinting using spoligotyping, mycobacterial interspersed repetitive unit, and IS6110-based restriction fragment length polymorphism of culture-confirmed cases of TB was performed. Clinical and demographic factors associated with strain MS0006 were analyzed by univariate and multivariate analysis.
Of the 144 cases of TB diagnosed during the study period, 117 were culture positive with fingerprints available. There were 48 different strains, of which 6 clustered strains were distributed among 74 patients. The MS0006 strain accounted for 46.2% of all culture-confirmed cases. Risk factors for having the MS0006 strain in a univariate analysis included homelessness, HIV co-infection, sputum smear negativity, tuberculin skin test negativity, and noninjectable drug use. Multivariate analysis identified homelessness (odds ratio 7.88, 95% confidence interval 2.90-21.35) and African American race (odds ratio 5.80, 95% confidence interval 1.37-24.55) as independent predictors of having TB caused by the MS0006 strain of M. tuberculosis.
Our findings suggest that a majority of recently transmitted TB in the studied county was caused by the MS0006 strain. African American race and homelessness were significant risk factors for inclusion in the cluster. Molecular epidemiology techniques continue to provide in-depth analysis of disease transmission and play a vital role in effective contact tracing and interruption of ongoing transmission.
Southern medical journal 12/2011; 104(12):819-26. · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis (TB) remains a major cause of mortality despite availability of effective chemotherapy. This study was performed to identify contributing factors for poor outcome during anti-tuberculosis treatment at a teaching hospital chest clinic. Medical records of registered patients treated for TB between 1 January and 31 December, 2009 were reviewed and abstracted for demographic, clinical and outcome data. Risk factors for mortality during therapy were assessed using bivariate and multivariate logistics approaches. Of 599 patients, 355 (58.9%) completed therapy and/or were cured, 192 (32.1%) died, and 39 (6.5%) defaulted. In multivariate analysis, independent risk factors for mortality included pulmonary cases for which sputum smear status was unknown (odds ratio [OR] 13.7; 95% confidence interval [CI] 6.0, 31.4), HIV coinfection (OR, 3.6; 95% CI 2.4, 5.4), disseminated TB (OR, 2.2; 95% CI 1.0, 4.9), TB meningitis (OR, 2.8; 95% CI 1.5, 5.3), not having a treatment supporter (OR, 2.0; 95% CI 1.3, 3.1), and low body weight (OR, 11.0; 95% CI 3.1, 38.6). Not having a treatment supporter (OR, 3.2; 95% CI 1.6, 6.6) and HIV coinfection (OR, 2.4; 95% CI 1.2, 5.2) were also independently associated with treatment default. Our findings suggest that enhanced measures to reduce mortality and default in TB patients with HIV coinfection, disseminated or meningeal disease and those who have no treatment supporters may help improve treatment outcomes in Ghana.
Transactions of the Royal Society of Tropical Medicine and Hygiene 09/2011; 105(12):675-82. · 1.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Efavirenz-based antiretroviral regimen is preferred during rifampin-containing tuberculosis therapy. However, current pharmacokinetic data are insufficient to guide optimized concurrent dosing. This study aimed to better characterize the effects of rifampin on efavirenz pharmacokinetics. Subjects were randomized to receive 600 mg efavirenz/day or 600 mg efavirenz with 600 mg rifampin/day for 8 days, with plasma samples collected for pharmacokinetic analysis over 24 h on day 8. Treatments were then crossed over after at least a 2-week washout period, and procedures were repeated. Efavirenz concentrations were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were estimated by noncompartmental analysis. Efavirenz pharmacokinetic differences between treatment periods were evaluated by paired t test. The coefficients of variation in efavirenz plasma AUC(0-24) (area under the concentration-time curve from 0 to 24 h) were 50% and 56% in the absence and presence of rifampin, respectively. Of the 11 evaluable subjects (6 white, 5 black; 6 women, 5 men), the geometric mean AUC(0-24) ratio on/off rifampin (90% confidence interval) was 0.82 (0.72, 0.92), with individual AUC(0-24) ratios varying from 0.55 to 1.18. Five subjects had a 24-hour efavirenz concentration (C(24)) of <1,000 ng/ml on rifampin. They were more likely to have received a lower dose in milligrams/kilogram of body weight and to have lower efavirenz AUC(0-24) values in the basal state. Although rifampin resulted in a modest reduction in efavirenz plasma exposure in subjects as a whole, there was high variability in responses between subjects, suggesting that efavirenz dose adjustment with rifampin may need to be individualized. Body weight and genetic factors will be important covariates in dosing algorithms.
Antimicrobial Agents and Chemotherapy 07/2011; 55(7):3527-33. · 4.57 Impact Factor
[Show abstract][Hide abstract] 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.
Journal of clinical microbiology 03/2011; 49(3):834-44. · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Viral decay rates during efavirenz-based therapy were compared between human immunodeficiency virus (HIV)-infected patients without tuberculosis (n = 40) and those with tuberculosis coinfection who were receiving concurrent antituberculous therapy (n = 34). Phase I and II viral decay rates were similar in the 2 groups (P > .05). Overall, concurrent antituberculous therapy did not reduce the efficacy of the HIV treatment.
[Show abstract][Hide abstract] ABSTRACT: 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 patient's genotype.
AIDS (London, England) 01/2011; 25(3):388-90. · 4.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The burden of paediatric HIV infection remains high in resource-poor settings. Information on morbidity leading to hospitalisation as well as outcome is limited.
The objective of this study was to determine the reasons for hospital admissions of HIV-infected paediatric patients to a tertiary teaching hospital and the outcome of these admissions.
Retrospective chart review of inpatient records of all HIV-infected children aged 0 to 13 years admitted to the paediatric unit at Korle-Bu Teaching Hospital from 30 June 2007 to 30 June 2008 was performed. Abstracted data included age, gender, weight, presenting conditions, diagnosis, duration of hospitalisation, antiretroviral treatment, and outcome.
A total of 102 admissions occurred among 76 children. The mean age of the children was 4.5 ± 3.79 years and 42 (55%) were males. HIV diagnosis was made during hospitalisation in 23 (30%) of the 76 patients. Overall, 55 (64%) of the 76 patients had a weight for age less than second percentile and 67% were not on antiretroviral therapy at time of admission. Of the 102 admissions, the predominant diagnosis included pneumonia (40%), gastroenteritis (24%), pulmonary tuberculosis (22%), and/or malaria (19%). Death occurred in 12 of the 102 admissions. Age, gender, and admitting diagnosis were not associated with death.
Failure to thrive and common prevalent infections were the predominant reasons for hospitalisation for paediatric HIV/AIDS patients in Accra. Hospitalisations with these conditions should prompt early HIV testing. Efforts should be intensified to prevent maternal to child transmission of HIV infection.
West African journal of medicine 01/2011; 29(6):379-83.
[Show abstract][Hide abstract] ABSTRACT: This study investigated the immunologic responses and employment history of highly-active antiretroviral therapy (HAART) patients.
We interviewed patients and reviewed medical records to collect demographic, clinical, and employment history while on HAART. Demographic characteristics were tested as predictors of immunological response while on HAART using hierarchical linear models.
Fevers Unit, Korle-Bu Teaching Hospital, Accra, Ghana
Subjects comprised a convenience sample of adult HAART patients receiving therapy for at least 9 months. 270 patients were interviewed. 38 were excluded due to inadequate time on HAART or inability to locate all necessary patient information.
This was an observational study. Main outcome measures: We investigated the change in CD4 cell count and weight since the initiation of therapy, and their ability to maintain or regain employment as well as the reasons for this.
The estimated mean ± standard error increase in CD4 cell count from baseline at 6, 12, and 18 months were 102 ± 5, 204 ± 11, and 236 ± 10 cells/µL, respectively. Overall, 147 patients (63.4%) reported remaining employed or obtaining new employment while on HAART. Patients who were asymptomatic at initial presentation were more likely to remain employed or returned to work while on HAART than those who were symptomatic (66.4% vs. 48.8%, P = 0.009). Most patients were employed in the informal sector, which made their economic situation particularly vulnerable to HIV-associated illness.
The findings suggest that patients receiving HAART experience good clinical and immunological responses as well as improvement in employment status.
[Show abstract][Hide abstract] ABSTRACT: The burden of MDR-TB is unknown in areas that do not have drug susceptibility testing (DST), but its frequency is expected to be higher in previously treated cases. Where DST is not available the WHO recommended standardized retreatment (Category II) regimen is given to previously treated TB patients
To evaluate the frequency and pattern of drug resistance of Mycobacterium tuberculosis isolated from patients with chronic smear positive pulmonary tuberculosis.
We conducted a retrospective review of mycobacterial cultures and drug susceptibility testing (DST) performed on sputum samples collected, between January 2005 and September 2006, from 40 patients with pulmonary TB who had failed at least one standard retreatment regimen. Clinical data was extracted from patients' case notes.
M. tuberculosis was recovered from 28 (70%) of the 40 patients. Of the 28 culture positive cases, 10 (36%) had resistance to at least rifampicin and isoniazid (multi-drug resistant TB), 22 (79%) isolates had resistance to streptomycin and 13 (46%) to ethambutol. Of the patients with a positive culture, only one (3.6%) had a fully susceptible organism. Of the 10 patients with MDR TB, 7 had received two or more retreatment courses.
The frequency of drug resistant TB was high among patients who failed at least one course of category II therapy. Effective combination regimens based on DST is necessary in patients who remain smear positive on the standardized retreatment regimen.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Expert Opinion on Drug Metabolism & Toxicology 12/2009; 6(1):55-68. · 2.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
AIDS (London, England) 09/2009; 23(16):2101-6. · 4.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 in UGT2B7*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.
The Journal of Clinical Pharmacology 08/2009; 49(9):1079-90. · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
British Journal of Clinical Pharmacology 04/2009; 67(4):427-36. · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 microg x h/mL, P< .0001) or GG genotype (107 vs 23.0 microg x 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.
The Journal of Clinical Pharmacology 09/2008; 48(9):1032-40. · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present the case of an HIV-infected patient with cirrhosis in whom severe neuropsychiatric signs and symptoms developed in the setting of a significantly elevated plasma efavirenz level. Although mild neuropsychiatric symptoms are a well-known adverse effect of this medication, to our knowledge, this is the first report of status epilepticus with routine efavirenz dosing. This case raises several significant questions regarding the adverse effects and dosing of this medication, including which patient characteristics predispose to efavirenz toxicity, the relevance of the CYP2B6 mutation, and indications for therapeutic drug monitoring.
The AIDS reader 07/2008; 18(7):386-8, C3. · 0.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The treatment of latent tuberculosis infection (LTBI) is essential for tuberculosis elimination in the United States, but the major limitation is poor adherence to therapy. To aid the design of targeted adherence interventions, we investigated the factors associated with noncompletion of isoniazid (INH) therapy for LTBI.
A retrospective analysis of patients with who failed to complete vs those who completed 9 months of INH therapy at the RISE TB Clinic (Miriam Hospital; Providence, RI) in 2003 was performed. Factors associated with treatment noncompletion were examined using univariate and multiple logistic regression analysis.
Of 845 patients with LTBI, 690 patients (81.6%) initiated INH therapy, of whom 426 patients (61.7%) completed therapy, and 246 patients (35.6%) were lost to follow-up. Treatment was discontinued in 18 patients (2.6%). Patients who failed to complete therapy were younger (mean age, 30.6 vs 33.8 years, respectively; p = 0.006), and were more likely to be uninsured (42.9% vs 29.8%, respectively; p = 0.0004), to be postpartum (66.7% vs 37.3%, respectively; p = 0.043), and to report treatment side effects (54.8% vs 30.1%, respectively; p < 0.0001). Reported treatment side effects (odds ratio [OR], 3.6; 95% confidence interval [CI], 2.2 to 6.2) and lack of medical insurance (OR, 1.7; 95% CI, 1.1 to 2.7) were each associated with treatment noncompletion in a model including both. Also, pregnant women were more likely than nonpregnant women to fail to initiate INH treatment (52.1% vs 14.7%, respectively; p < 0.0001).
LTBI patients who are young, pregnant or postpartum, uninsured, and/or report treatment side effects may require additional case management to improve INH treatment completion rates.