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PHARMACOGENOMICS

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

Awewura Kwara, MBChB, MPH&TM, Margaret Lartey, MBChB, FWACP, Kwamena W. Sagoe, MSc, Fafa Xexemeku, MBChB, Ernest Kenu, MBChB, Joseph Oliver-Commey, MBChB, Vincent Boima, MBChB, Augustine Sagoe, BSc, Isaac Boamah, BSc, David J. Greenblatt, MD, FCP and Michael H. Court, BVSc, PhD

From The Miriam Hospital, Providence, Rhode Island (Dr Kwara); Warren Alpert Medical School of Brown University, Providence, Rhode Island (Dr Kwara); University of Ghana Medical School, Accra, Ghana (Dr Lartey, Mr Sagoe, Mr Boamah), Korle-Bu Teaching Hospital, Accra, Ghana (Dr Xexemeku, Dr Kenu, Dr Oliver-Commey, Dr Boima, Mr Sagoe); and Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts (Dr Greenblatt and Dr Court).

Address for reprints: Awewura Kwara, MD, The Miriam Hospital, 164 Summit Avenue, Providence, RI 02906; e-mail: akwara{at}lifespan.org.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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 µgxh/mL, P < .0001) or GG genotype (107 vs 23.0 µgxh/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.

Key Words: Cytochrome P450 2B6 • genetic polymorphisms • efavirenz exposure • rifampin

Tuberculosis (TB) is the most common complication of human immunodeficiency virus (HIV) infection and is associated with high fatality rates.1,2 While highly active antiretroviral therapy (HAART) improves survival in co-infected patients,3-5 potential overlapping drug toxicities and cytochrome P450 (CYP)–mediated drug–drug interactions constitute major challenges to early initiation of HAART. The magnitude of drug–drug interactions due to rifampin is a major factor in selecting an effective HAART regimen.6-8 Rifampin is a critical component of TB therapy9 but is also a potent inducer of CYP enzyme activity10-12 as well as the P-glycoprotein (P-gp) transport system.13 As a result, the exposure to the HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) is reduced during concomitant rifampin therapy.6-8 The reduction in exposure is more pronounced for the PIs, and often co-administration with rifampin is contraindicated.6-8 Of the NNRTIs, current treatment guidelines consider the interactions between rifampin and efavirenz to be manageable, and an efavirenz-based regimen is preferred in patients on rifampin.6-8

Efavirenz is primarily metabolized by hepatic CYP2B6, with minor contributions from CYP3A4/5 and CYP2A6.14,15 In the setting of impaired CYP2B6 function, it is hypothesized that alternate metabolic pathways are critical for the clearance of efavirenz.16 The CYP2B6 gene is highly polymorphic17 and is subject to pronounced interindividual variability in expression and activity. The single nucleotide polymorphism (SNP) c.516G>T (Q172H), a marker for the CYP2B6*6*6 [Q172H and c.785A>G (K262R)] allele, is significantly associated with elevated efavirenz plasma concentrations18-22 and a higher likelihood of efavirenz-related central nervous system (CNS) symptoms.21,22 The low clearance of efavirenz in CYP2B6*6*6 haplotype has been associated with a reduced CYP2B6 protein expression in the liver.15

It is not known whether CYP induction by rifampin will affect the relationship between CYP2B6 c.516G>T genotype and efavirenz exposure. The reported magnitude of induction of CYP2B6 activity by rifampin in primary human hepatocytes varies. While some authors reported a 7- to 13-fold induction,10,11 others found only a 2.5-fold increase in activity.12 In one in vivo study, CYP2B6 activity in the presence of rifampin was only 2.1 times that in the absence of rifampin.23 Co-administration of rifampin with efavirenz 600 mg/d caused a 22% reduction in efavirenz area under the curve (AUC) in HIV/TB co-infected patients, which was overcome by increasing the dose to 800 mg/d.24 This finding led some experts to recommend an increased dose of efavirenz when co-administered with rifampin.6,7,25 Although an increased efavirenz dose might be appropriate for some persons, it does not take into consideration the variable effect of rifampin on CYP2B6 activity. In the aforementioned pharmacokinetic study, the change in efavirenz AUC with concomitant rifampin ranged from a decrease of 65% to an increase of 37%.24 Furthermore, variability in efavirenz concentrations is greater in the presence of rifampin than without rifampin.26,27

The CYP2B6 genotype most frequently associated with the slow-metabolizer phenotype (c.516TT) occurs with high frequency in native African populations,28,29 and dose reduction has been proposed in patients with this variant.29 Globally, efavirenz-based HAART is often needed in HIV/TB co-infected patients on rifampin. Consequently, understanding the potential modifying influence of enzyme induction and CYP2B6 genetic polymorphisms could enhance optimization of efavirenz dosage.

In this study, we determined whether the CYP2B6 c.516G>T genotype is predictive of efavirenz plasma concentrations in TB/HIV co-infected patients on rifampin. To our knowledge, this is the first study to evaluate whether variability in efavirenz exposure during co-administration with rifampin is related to CYP2B6 polymorphisms.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Study Design and Patients
A steady-state pharmacokinetic study of efavirenz was performed in HIV and TB co-infected patients in Ghana, West Africa. HIV/TB co-infected patients with CD4 count ≤250 cells/mm3 receiving rifampin therapy were prospectively enrolled between November 2005 and February 2007. Patients aged 18 years or older were considered for inclusion if they were antiretroviral therapy naïve, had a new diagnosis of TB in the induction phase of therapy, and were available for follow-up at the study site for antiretroviral therapy. Patients were excluded if they were pregnant or breast-feeding, had any other opportunistic infections within 30 days of study entry, and had a hemoglobin count <6 g/dL, leukocyte count <2500/mm3, serum creatinine >1.5 mg/dL, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 times upper limit of normal. All females with the potential for pregnancy were required to use 2 nonhormonal methods of contraception.

Tuberculosis diagnosis was based on a positive sputum smear for acid-fast bacilli (AFB) or a clinical presentation consistent with active disease. All patients received antituberculosis therapy consisting of isoniazid 5 mg/kg (maximum 300 mg) daily, rifampin 10 mg/kg (maximum 600 mg) daily, pyrazinamide 25 mg/kg (2 g daily), and ethambutol 15 mg/kg (maximum 2 g) daily for at least 2 months, followed by isoniazid and ethambutol daily for 6 to 10 months in accordance with Ghana National TB treatment guidelines in 2005. HAART was started between 2 and 10 weeks of starting TB therapy. The HAART regimen consisted of efavirenz 600 mg/d plus either lamivudine 150 mg and zidovudine 300 mg twice daily or lamivudine 150 mg and stavudine 40 mg twice daily for those with hemoglobin ≤8 g/dL. The Institutional Review Board for the protection of human subjects of the University of Ghana Medical School, Ghana, and Lifespan Hospitals, Providence, Rhode Island, reviewed and approved the study protocol.

Clinical and Laboratory Monitoring
Each participant was evaluated at study entry, and relevant clinical data were collected using standardized forms. Baseline measurements of complete blood count, blood urea nitrogen, serum creatinine, liver function, CD4 cell count, and HIV-1 plasma viral load were done prior to starting HAART. All study participants were reevaluated at week 2 of HAART and at 1 month. Drug-related side effects, clinical responses, and medication adherence were recorded at follow-up visits. Hemoglobin and liver function tests were repeated at 1 month of HAART, and toxicity was graded according to the Division of AIDS table for grading severity of adult adverse experiences.30

Pharmacokinetic Sampling
Pharmacokinetic sampling was performed on day 14 of concurrent HAART. The median duration of rifampin therapy before initiation of HAART was 35 days (range, 14-70 days). Patients were instructed to switch their evening efavirenz administration to mornings 3 days prior to admission to the hospital for sampling. Blood samples were obtained prior to medication dosage and at times 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after observed administration of antituberculous and antiretroviral drugs. Seven milliliters to 10 mL of blood was collected in heparinized plastic tubes and then centrifuged at 3000 g for 10 minutes. Plasma was separated into labeled 1.2-mL cryovials and frozen at –70°C until shipping. The frozen plasma samples were shipped on dry ice for analysis and were received in good condition. Plasma samples were stored at –70°C until testing.

Analytical and Pharmacokinetic Analysis
Efavirenz concentrations were determined by a modified validated reverse-phase high-performance liquid chromatography with an ultraviolet absorbance detector.31 Ritonavir (Norvir, Abbott Laboratories, Abbott Park, IL) was used as the internal standard. The retention times of the internal standard and efavirenz were 9.9 and 16.9 minutes, respectively. Calibration curves were linear in the range of 0.05 to 12.5 µg/L (mean R2 = 0.992; SD = 0.003), and the limit of detection was 0.05 µg/L. Recovery of efavirenz ranged from 110% to 120%. Intraday variability (expressed as a coefficient of variation) ranged from 8.8% to 13.7%, whereas interday variability ranged from 10.8% to 14.3%.

CYP2B6 Genotyping
Exons 4, 5, and 7 of CYP2B6 gene were sequenced to determine the c.516G>T (Q172H, rs3745274), c.785G>A (K262R, rs2279343), and c.983T>C (I328T, rs28399499) c.SNP genotypes in each study participant. We chose these SNPs because they are relatively common in native Africans populations and have been associated with altered CYP2B6 function in vivo18-22 and in vitro.15 Because we used direct sequencing for genotyping, it was also possible to evaluate whether rarer cSNPs reported in African populations with established effects on CYP2B6 function were also present including c.1006C>T (R336C, rs34826503), c.503C>T (T168I, rs36056539), and c.593T>C (M198T, rs36079186). Genomic DNA was isolated from blood spots collected on Whatman FTA Classic Cards (Whatman International Ltd, Kent, UK) according to the manufacturer's protocol. Polymerase chain reaction was performed using 3 sets of primers designed to amplify target exons including exon–intron boundaries. The primers used were GGT CTG CCC ATC TAT AAA C (forward) and CTG ATT CTT CAC ATG TCT GCG (reverse) for exon 4; ACA GCA AGG GAG ATG AGG AGA GGT (forward) and TCT TTC TGC CTC TGT GAG TTT TTT CTC T (reverse) for exon 5; and AAT CCA CCC ACC TCA ACC TCC AAA AT (forward) and CCA AAC AGG AGG GCT ATG GGG (reverse) for exon 7. SNP genotypes were determined by direct inspection of sequence chromatograms (FinchTV, Geospiza, Inc, Seattle, Wash) and were used to infer the CYP2B6*1*1 (reference), CPY2B68*1*4 (K262R), CPY2B6*6*6 (Q172H, K262R), CPY2B6*1*9 (Q17H), CPY2B6*1*16 (K262R, I328T), and CPY2B6*1*18 (I328T) haplotypes for each subject (http://www.cypalleles.ki.se/cyp2b6.htm).

Pharmacokinetic Analysis
Peak plasma concentration (Cmax), time to Cmax (Tmax), concentration at 12 hours (C12h), and trough concentration at 24 hours (Cmin) were obtained by visual inspection of the plasma efavirenz concentration–time profile for each patient. Other pharmacokinetic parameters were determined by noncompartmental methods from plasma drug concentration–time data. The AUC from time zero to 24 hours (AUC0-24h) was determined using the trapezoidal method. Apparent oral clearance of efavirenz (CL/F) was calculated by dividing the administered efavirenz daily dose (600 mg) by the AUC0-24h. Clearance was normalized to body weight (CL/F/W) at study entry in kilograms.

Statistical Analysis
All statistical analyses were performed using Sigmastat 3.0 software (Systat, San Jose, Calif). Values of AUC0-24h, Cmax, Cmin, CL/F, and CL/F/W among CYP2B6 c.516GG, GT, and TT groups were compared using Kruskal-Wallis analysis of variance (ANOVA) on ranks. Individual groups were pairwise compared using the Student-Newman-Keuls procedure with adjustment for multiple comparisons. Correlations between efavirenz AUC0-24h and Cmin and between efavirenz AUC0-24h and C12h were evaluated by Spearman correlation analysis. Genotype frequencies were tested for consistency with expected Hardy-Weinberg equilibrium by chi-square test.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Study Population
Between January 2006 and February 2007, 55 patients with TB/HIV co-infection were screened for inclusion in the study. Of these, 25 patients met at least 1 exclusion criteria. Of 25 patients excluded from the study, 10 patients had ALT or AST levels >2 times the upper limit of normal, 7 died before consent, 4 had total white blood cell count <2.5, and 4 had elevated serum creatinine >1.5 mg/dL.

Of the 30 enrolled patients, 26 completed both pharmacogenetic and pharmacokinetic testing. The demographic and baseline characteristics of the 26 patients who were included in the final analysis are summarized in Table I. The mean age was 39 years (range, 22-54 years), 18 patients (69.2%) were males, 16 patients (62.0%) had a history of alcohol ingestion, and the mean body weight was 55.7 kg. There were no differences in baseline characteristics between patients in the 3 major CYP2B6 c.516G>T genotypic groups (Table I).


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  		Table I Baseline Characteristics of the 26 Tuberculosis and Human Immunodeficiency Virus Co-infected Patients Who Completed the Study

 
Frequency of CYP2B6 Genotypes and Haplotypes
We first analyzed for CYP2B6 genotypic variants of the nonsynonymous c.516G>T exon 4 c.SNP for all 30 enrolled patients and found the GG genotype in 8 patients (27.0%), GT genotype in 15 patients (50.0%), and TT genotype in 7 patients (23.0%), which is consistent with the predicted Hardy-Weinberg distribution ({chi}2 = 0.00004; P = .995). Additional genotype analysis of the exons 5 and 7 c.SNPs enabled unambiguous haplotype inference for 5 different alleles, including CYP2B6*1*1 (reference), CYP2B6*1*4 (K262R), CYP2B6*6*6 (Q172H, K262R), CYP2B6*1*9 (Q172H), and CYP2B6*1*18 (I328T) (Table II). The most common CYP2B6 haplotypes in the 30 patients studied were CYP2B6*1*6 (13 patients), CYP2B6*6*6 (7 patients), and CYP2B6*1*1 (5 patients). Rarer haplotypes included CYP2B6*1*18 (2 patients), CYP2B6*1*4 (1 patient), and CYP2B6*1*9 (1 patient). One patient was heterozygous for all 3 c.SNPs and so was either CYP2B6*1*16 or CYP2B6*6*18 (Table II). We did not find any of the rarer exon 4 or exon 5 c.SNPs in any of the subjects.


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  		Table II Frequency of CYP2B6 516G>T Genotypes and Haplotypes in 30 Enrolled Patients With Tuberculosis and Human Immunodeficiency Virus Co-infection in Ghana

 
Efavirenz Concentrations and CYP2B6 Genotype Correlations in the Presence of Rifampin
The variability in total plasma efavirenz exposure was 110% and was strongly associated with CYP2B6 c.516G>T genotype. Efavirenz AUC, Cmax, and Cmin values were all significantly higher in patients with the c.516TT genotype compared to subjects with either the c.516GG or c.516GT genotypes (Figure 1A, Table III). However, there were no statistically significant differences in efavirenz concentrations and AUC0-24h between the patients with c.516GT and c.516GG genotypes. The inclusion of K262R and I328T SNPs into the phenotype–genotype analysis (as haplotypes) did not improve prediction of the slow metabolizer phenotype over c.516G>T alone (Figure 1B). Apparent oral clearance of efavirenz (CL/F) and CL/F normalized for body weight were significantly lower in patients with c.516TT genotype than in those with c.516GG or c.516GT genotypes, but no differences were found between those with c.516GT compared with c.516GG (Table III).


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  		Table III Steady-State Pharmacokinetic Parameters of Efavirenz in 26 Tuberculosis and Human Immunodeficiency Virus Co-infected Patients Receiving Rifampin Stratified by CYP2B6 c.516G>T Genotype

 
Further phenotype–genotype analysis of data from individuals with the most common CYP2B6 haplotypes (*1*1, *1*6, and *6*6) indicated that patients with CYP2B6*6*6 haplotype had significantly higher AUC than those with the CYP2B6*1 *1 or CYP2B6*1*6 haplotypes (Figure 2). Because of the relatively low frequency of the remaining haplotypes, with 1 patient each, it was not possible to test differences for statistical significance (Figure 2).


Figure 1
Figure 1
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  		Figure 1. Mean (±SEM) efavirenz concentrations at each timed point stratified by CYP2B6 c.516G>T genotype (A) and by CYP2B6 haplotype (B) in HIV/tuberculosis (TB) co-infected patients receiving rifampin-containing TB treatment. Efavirenz concentrations at all time points were significantly higher in patients with CYP2B6 c.516TT than those with GG or GT genotypes.

 
Safety and Tolerability
There was one death that was attributed to extensive pulmonary TB in a patient who had already received 2 months of TB treatment before initiation of HAART. Drug susceptibility testing was not available to determine whether this patient had resistant TB. Two patients (CYP2B6 c.516GG and c.516GT genotypes) developed grade 2 AST and ALT abnormalities, whereas 1 patient (c.516GT genotype) developed a grade 3 hemoglobin abnormality at week 4. None of the patients discontinued TB therapy or HAART as a result of adverse treatment effects.


Figure 2
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  		Figure 2. Efavirenz AUC0-24h values stratified by CYP2B6 c.516G>T genotype (A) and by CYP2B6 haplotype (B) in HIV/tuberculosis (TB) co-infected patients receiving rifampin-containing TB treatment. Genotype and haplotype group differences were evaluated by Kruskal-Wallis analysis of variance on ranks with pairwise group comparisons by the Student-Newman-Keuls procedure. Horizontal bars represent the median.

 
Correlation Between Timed Discrete Efavirenz Concentrations and AUC0-24h
Finally, we evaluated the correlation between dosagetimed efavirenz concentrations including Cmin and C12h, which are more convenient for therapeutic drug monitoring of efavirenz therapy than AUC0-24h. As shown in Figure 3, we found strong linear correlations between both Cmin and AUC0-24h (Rs = 0.962, P < .0001) and also between C12h and AUC0-24h and Cmin (Rs = 0.969, P < .0001).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
Our findings show that the wide interindividual variability of efavirenz concentrations in rifampin-treated HIV/TB co-infected patients is strongly associated with CYP2B6 c.516TT genotype status. A substantial number of pharmacogenetic studies of efavirenz disposition conducted previously found significant differences in efavirenz concentrations in patients associated with CYP2B6 c.516G>T genotype with the rank order of c.516TT > GT > GG genotype.18-22 However, none of these studies were performed in the presence of rifampin and it was not clear what effect this drug would have on the CYP2B6 genotype–phenotype relationship. Although we did not find an intermediate phenotype for CYP2B6 c.516GT genotype as previously established,18-22 the c.516TT genotype was strongly predictive of high efavirenz exposure in patients with TB/HIV who are taking rifampin.


Figure 3
Figure 3
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  		Figure 3. Correlations between efavirenz AUC0-24h and Cmin (A) and between efavirenz AUC0-24h and C12h (B). Also shown on each plot are the fitted lines and Spearman correlation coefficients (Rs) and P values.

 
We had hypothesized that rifampin co-administration would minimize differences in efavirenz clearance related to CYP2B6 genotype either through enhancement of residual CYP2B6 activity in those individuals with the intermediate and normal metabolizer genotypes (CYP2B6 c.516 GT and GG) or perhaps via induction of alternate efavirenz clearance pathways, including CYP enzymes (other than CYP2B6) that metabolize efavirenz such as CYP3A4/5 and CYP2A6. In support of this contention, our results showed no difference in efavirenz clearance between individuals with the CYP2B6 c.516GT and GG genotypes. This contrasts with several previous studies in the absence of rifampin that showed a clear intermediate metabolizer phenotype with an average 24% to 27% lower clearance in CYP2B6 c.516GT heterozygotes versus c.516GG homozygotes.18-22

However, we also showed significantly lower efavirenz clearance in CYP2B6 c.516TT individuals, indicating that rifampin treatment does not fully reverse the poor metabolizer phenotype in this genotype group. Recent in vitro work indicates that the CYP2B6 c.516G>T polymorphism alters a splice enhancer site and results in aberrant messenger RNA (mRNA) splicing, with deletion of critical protein domains, and nonfunctional enzyme protein.32 Consequently, enhancement of CYP2B6 gene transcription via effects of rifampin on pregnane X receptor will lead to enhanced CYP2B6 mRNA, but much of this mRNA will likely be aberrantly spliced and will not produce active enzyme.

Efavirenz metabolism undergoes significant autoinduction following repeated dosing through constitutive androsterone receptor (CAR)–mediated enhancement of CYP2B6 gene expression.33,34 Other CAR-regulated CYPs such as CYP3A4 may also be induced with repeated efavirenz dosing. Consequently, it is possible that any additional effect of rifampin on efavirenz metabolism in our patients may be limited to those enzymes that are regulated mainly by pregnane X receptor and not by CAR. Furthermore, our patients may have been exposed to other potential enzyme inducers such as alcohol, which in previous work in our laboratory has been associated with enhanced CYP2B6 activity in vitro.35

A limitation of this study is that we did not include a comparator group of patients who had not received rifampin to determine whether there are differential effects of rifampin on each genotype. However, the average efavirenz oral clearance for patients in this study was 2.1 to 2.7 times higher than published values for subjects receiving a similar dose of efavirenz in the absence of rifampin.36,37 This is consistent with enhancement of efavirenz clearance by pregnane X receptor/constitutive androstane receptor–mediated induction of CYP2B6 protein expression,11,38-40 although it could also be the result of differences in the populations studied (sub-Saharan African in this study vs mostly Caucasians in the other studies).

We assayed for several c.SNPs other than c.516G>T (Q172H), including K262R and I328T, that have been associated with altered CYP2B6 activity. However, inclusion of these additional SNPs in the phenotype–genotype analysis (as haplotypes) did not improve prediction of the slow metabolizer phenotype over c.516G>T alone, either because of low frequency in the population (I328T) or linkage with c.516T as part of the CYP2B6*6 haplotype (K262R is in linkage with Q172H).

Although we measured complete efavirenz concentration profiles over 24 hours in order to accurately derive segmental AUC values, such intensive monitoring is not always practical, particularly for studies involving large patient populations. Consequently, we evaluated the correlation between AUC values and single plasma concentrations collected at defined time points relative to dose (Cmin and C12h). In both instances, excellent correlations were observed, validating the use of such measures as a surrogate for AUC in future (and previous) studies.

In conclusion, the results of this study demonstrate that CYP2B6 c.516TT genotype is highly predictive of reduced clearance of efavirenz in rifampin-treated TB/HIV co-infected patients. A priori dose reduction of efavirenz in patients with CYP2B6 516TT genotype or CYP2B6*6*6 haplotype with a goal of minimizing toxicity41 as well as reducing cost29 may be important, especially in resource-poor settings. Any controlled trials of reduced efavirenz dose in carriers of CYP2B6 516TT genotype should not exclude individuals requiring concurrent rifampin therapy, because co-administration does not appear to reverse the poor metabolizer phenotype associated with this genotype. Although our data suggest that the effect of rifampin on efavirenz clearance might differ depending on patient CYP2B6 genotype, the lack of an appropriate control group limits any firm conclusions. Consequently, a controlled 2-way crossover pharmacokinetic interaction study examining the effect of rifampin within each subject is currently underway to directly address this hypothesis.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
We thank the study participants; the study coordinator, Adjoa Obo-Akwa, and her assistant, Esther Manche; and the study nurse, Janet May Ayi of Korle Bu Teaching Hospital. We are grateful to Aba Hayford and Makafui Seshie of Clinical Virology, UGMS, for laboratory support. We thank Drs Charles Carpenter and Timothy Flanigan as well as Vicki Godleski of Lifespan/Tufts/Brown CFAR for valuable comments and administrative support and Dr David Haas for comments on the manuscript.

DOI: 10.1177/0091270008321790

Dr Hartmut Derendorf acted as editor for this article.

Financial disclosure: This research was funded in part by a 2004 developmental grant from the Lifespan/Tufts/Brown Center for AIDS Research and NIH K23 developmental award (NIH K23 AI071760) to Dr Kwara. The project described was supported by grant P30AI042853 from the National Institute of Allergy and Infectious Diseases. Dr Greenblatt is supported by grants AG-17880 and AI-58784, and Dr Court is supported by grants GM-74369 and GM-61834 from the Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institute of Health. Dr Kwara has received research funding from Bristol-Myers Squibb and is a member of the speaker's bureau. The other authors declare no conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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G. Ramachandran, A. K. Hemanth Kumar, S. Rajasekaran, P. Kumar, K. Ramesh, S. Anitha, G. Narendran, P. Menon, C. Gomathi, and S. Swaminathan
CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India
Antimicrob. Agents Chemother., March 1, 2009; 53(3): 863 - 868.
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