Efavirenz Plasma Concentrations and Cytochrome 2B6 Polymorphisms
ANNALS OF PHARMACOTHERAPY
2010; 44 (10): 1572-1578
Efavirenz-induced hypersensitivity reaction manifesting in rash and hepatitis in a Latino male
ANNALS OF PHARMACOTHERAPY
2008; 42 (3): 425-429
Interpatient variability in efavirenz concentrations may be due to CYP2B6 genetic polymorphisms. Efavirenz concentration and pharmacogenomic data are scarce in Latino patients.To evaluate the difference in trough and midpoint efavirenz plasma concentrations between HIV-positive Latino and white patients. In addition, this study evaluated the association between efavirenz concentrations and CYP2B6 polymorphisms in Latino and white HIV-positive subjects.This pilot study included 10 Latinos and 10 whites. Two efavirenz blood concentrations were determined: a trough and a midpoint. CYP2B6 genetic polymorphisms were analyzed at the 516 (G to T) and 785 (A to G) codons. The Mann-Whitney test was used to determine whether efavirenz concentrations varied with ethnicity. The Kruskal-Wallis test was used to determine whether efavirenz concentrations varied with CYP2B6 genetic polymorphisms. Efavirenz concentrations were expressed as medians (minimum, maximum).Midpoint concentrations were 1.58 ?g/mL (1.36, 6.02) and 3.14 ?g/mL (1.74, 7.72) for whites and Latinos, respectively (p < 0.05). Trough concentrations did not vary as a function of ethnicity. Ten percent of Latinos and whites tested positive for homozygous variants of CYP2B6-516 and CYP2B6-785. One white subject tested positive for the homozygous variant of CYP2B6-1459. Trough concentrations for 516TT, 516GT, and 516GG (wild type) were 5.13 ?g/mL (4.13, 6.12), 2.13 ?g/mL (1.33, 3.37), and 1.44 ?g/mL (0.59, 2.92), respectively (p < 0.05). Trough concentrations for 785GG, 785AG, and 785AA (wild type) were 5.12 ?g/mL (4.13, 6.12), 1.98 ?g/mL (1.33, 3.37), and 1.27 ?g/mL (0.59, 2.92), respectively (p < 0.05). None of the patients took concomitant medications that impacted CYP2B6 metabolism.Trough efavirenz concentrations were significantly higher in patients with the 785 (A to G) and 516 (G to T) variants. Midpoint efavirenz concentrations in Latinos were significantly higher than those of whites.
View details for DOI 10.1345/aph.1P141
View details for Web of Science ID 000282675100006
View details for PubMedID 20841522
Treating the enemy.
Annals of internal medicine
2007; 147 (4): 278-279
Wind, rain, flooding, and fear: Coordinating military public health in the aftermath of Hurricane Katrina
CLINICAL INFECTIOUS DISEASES
2005; 41 (12): 1759-1763
To report a case of hypersensitivity manifesting in a rash, fever, and life-threatening hepatitis in a patient initiated on efavirenz therapy.A 30-year-old Latino male newly diagnosed with HIV was started on efavirenz-based highly active antiretroviral therapy (HAART) using tenofovir 300 mg, emtricitabine 200 mg, and efavirenz 600 mg once daily. Eleven days after beginning therapy, he developed a hypersensitivity reaction manifesting in rash and fever preceding severe drug-induced hepatitis. Liver enzyme peak values were aspartate transaminase 3410 U/L and alanine transaminase 2132 U/L. Hepatitis resolved with discontinuation of the HAART. The patient was rechallenged with tenofovir and emtricitabine one year later; no adverse reactions occurred.The Naranjo probability scale demonstrated a probable relationship between this adverse reaction and efavirenz. A MEDLINE search (2004 to September 2007) revealed 2 cases of rash preceding hepatitis with the initiation of efavirenz. Both cases were in women; there were no prior reported cases of efavirenz hypersensitivity in men. Although the mechanism of this reaction is unknown, a few factors may have contributed to this reaction. The half-life and the auto-induction of efavirenz may explain the continued rise in liver enzymes and severe hepatitis that continued to occur once the drug was discontinued. Another cause that may have contributed is the metabolism of the medication. CYP2B6 is responsible for almost 90% of the clearance of efavirenz. Data from a recent pharmacokinetic study showed that efavirenz concentrations were higher in both black and Latino patients when compared with those of white patients. In addition, it is highly probable that this patient's liver function was impaired when transaminase levels peaked, resulting in decreased clearance of efavirenz.Although such a hypersensitivity reaction is rare, efavirenz is the most probable cause of the erythematous maculopapular rash and acute hepatitis in this patient. Monitoring of liver function in patients who present with a rash following initiation of efavirenz-based HAART is recommended. In addition, clinicians should exercise caution in patients presenting with rash, fever, and increased liver enzymes (> 3 times the upper limit of normal or patient baseline). It is strongly recommended that efavirenz therapy be withheld in such cases and reevaluated once liver enzyme levels stabilize.
View details for DOI 10.1345/aph.1K574
View details for Web of Science ID 000254000200017
View details for PubMedID 18252833
HIV-1 protease and reverse transcriptase mutation patterns responsible for discordances between genotypic drug resistance interpretation algorithms
JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
2003; 33 (1): 8-14
On 29 August 2005, a category 4 hurricane struck the Gulf Coast of Mississippi and southeast Louisiana, resulting in widespread destruction caused by winds in excess of 190 km/h (120 miles/h), heavy rain, and flooding. Communication, electricity, and fresh water supplies were disrupted throughout the region, rendering much of the area uninhabitable. Despite tremendous obstacles, the US military spearheaded the eventually successful rescue, recovery, and relief operations. This article describes the challenges of protecting the health and safety of these personnel in the immediate aftermath of Hurricane Katrina.
View details for Web of Science ID 000233698300012
View details for PubMedID 16288401
Accuracy of the TRUGENE HIV-1 genotyping kit
JOURNAL OF CLINICAL MICROBIOLOGY
2003; 41 (4): 1586-1593
Several rules-based algorithms have been developed to interpret results of HIV-1 genotypic resistance tests. To assess the concordance of these algorithms and to identify sequences causing interalgorithm discordances, we applied four publicly available algorithms to the sequences of isolates from 2,045 individuals in northern California. Drug resistance interpretations were classified as S for susceptible, I for intermediate, and R for resistant. Of 30,675 interpretations (2,045 sequences x 15 drugs), 4.4% were completely discordant, with at least one algorithm assigning an S and another an R; 29.2% were partially discordant, with at least one algorithm assigning an S and another an I, or at least one algorithm assigning an I and another an R; and 66.4% displayed complete concordance, with all four algorithms assigning the same interpretation. Discordances between nucleoside reverse transcriptase inhibitor interpretations usually resulted from several simple, frequently occurring mutational patterns. Discordances between protease inhibitor interpretations resulted from a larger number of more complex mutation patterns. Discordances between nonnucleoside reverse transcriptase inhibitor interpretations were uncommon and resulted from a small number of individual drug resistance mutations. Determining the clinical significance of these mutation patterns responsible for interalgorithm discordances will improve interalgorithm concordance and the accuracy of genotypic resistance interpretation.
View details for Web of Science ID 000182805400002
View details for PubMedID 12792349
Drug resistance and poor virological responses are associated with well-characterized mutations in the viral reading frames that encode the proteins that are targeted by currently available antiretroviral drugs. An integrated system was developed that includes target gene amplification, DNA sequencing chemistry (TRUGENE HIV-1 Genotyping Kit), and hardware and interpretative software (the OpenGene DNA Sequencing System) for detection of mutations in the human immunodeficiency virus type 1 (HIV-1) protease and reverse transcriptase sequences. The integrated system incorporates reverse transcription-PCR from extracted HIV-1 RNA, a coupled amplification and sequencing step (CLIP), polyacrylamide gel electrophoresis, semiautomated analysis of data, and generation of an interpretative report. To assess the accuracy and robustness of the assay system, 270 coded plasma specimens derived from nine patients were sent to six laboratories for blinded analysis. All specimens contained HIV-1 subtype B viruses. Results of 270 independent assays were compared to "gold standard" consensus sequences of the virus populations determined by sequence analysis of 16 to 20 clones of viral DNA amplicons derived from two independent PCRs using primers not used in the kit. The accuracy of the integrated system for nucleotide base identification was 98.7%, and the accuracy for codon identification at 54 sites associated with drug resistance was 97.6%. In a separate analysis of plasma spiked with infectious molecular clones, the assay reproducibly detected all 72 different drug resistance mutations that were evaluated. There were no significant differences in accuracy between laboratories, between technologists, between kit lots, or between days. This integrated assay system for the detection of HIV-1 drug resistance mutations has a high degree of accuracy and reproducibility in several laboratories.
View details for DOI 10.1128/JCM.41.4.1586-1593.2003
View details for Web of Science ID 000182179900037
View details for PubMedID 12682149