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Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs

Author(s):
Moher, David, 1957-
Booth, Ronald A
United States Agency for Healthcare Research and Quality
University of Ottawa Evidence-based Practice Center
Title(s):
Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugsĀ [electronic resource] / prepared for Agency for Healthcare Research and Quality, U.S. Dept. of Health and Human Services ; prepared by University of Ottawa Evidence-based Practice Centre.; EPC director, David Moher ; investigators, Ronald A. Booth ... [et al.].
Series:
Evidence report/technology assessment ; no. 196
AHRQ publication ; no. 11-E002
Country of Publication:
United States
Publisher:
Rockville, MD : Agency for Healthcare Research and Quality, U.S. Dept. of Health and Human Services, [2010]
Description:
1 online resource (PDF (1 v.)) : ill.
Language:
English
Electronic Links:
http://www.ncbi.nlm.nih.gov/books/NBK55935
Summary:
OBJECTIVES: To examine whether pretreatment determination of thiopurine methyltransferase (TPMT) enzymatic activity (phenotyping) or TPMT genotype, to guide thiopurine therapy in chronic autoimmune disease patients, reduces treatment harms. Other objectives included assessing: preanalytic, analytic, and postanalytic requirements for TPMT testing; diagnostic accuracy of TPMT genotyping versus phenotyping; association of thiopurine toxicity with TPMT genotypic or phenotypic status; and costs of testing, care, and treating drug-associated complications. DATA SOURCES: MEDLINE(r), EMBASE(r), and Healthstar were searched from inception to May 2010; the Cochrane Library(r) to October 2009; and BIOSIS(r), Genetics Abstracts, and EconLitTM to May 2009, for English language records. REVIEW METHODS: A reviewer screened records, and a second reviewer verified exclusions and subsequent selection of relevant studies. Studies in patients with leukemia and organ transplant were excluded. Additionally, laboratories that provide TPMT analytical services were surveyed to assess means of TPMT testing in practice. Where possible, risk of bias was assessed using standard criteria. Meta-analyses estimated diagnostic sensitivity, and specificity; and odds ratios of associations. RESULTS: 1790 titles or abstracts, and 538 full text records were screened. 114 observational studies and one RCT were included. Majority of studies were rated fair quality, except for diagnostic studies with 37 percent of studies rated poor. In general, there were few patients who were homozygous (or compound heterozygous) for TPMT variant alleles in the included studies limiting applicability. There is insufficient evidence examining effectiveness of pretesting in terms of reduction in clinical adverse events. Sufficient preanalytical data were available regarding preferred specimen collection, stability and storage conditions for TPMT testing. There was no clinically significant effect of age, gender, various coadministered drugs, or most morbidities (with the exception of renal failure and dialysis). TPMT phenotyping methods had coefficients of variation generally below 10 percent. TPMT genotyping reproducibility is generally between 95-100 percent. The sensitivity of genotyping to identify patients with low or intermediate TPMT enzymatic activity is imprecise, ranging from 70.70 to 82.10 percent (95 percent CI, lower bound range 37.90 to 54.00 percent; upper bound range 84.60 to 96.90 percent). Sensitivity of homozygous TPMT genotype to correctly identify patients with low to absent enzymatic activity was 87.10 percent (95 percent CI 44.30 to 98.30 percent). Genotyping specificity approached 100 percent. Leukopenia was significantly associated with low and intermediate enzymatic activity (low activity OR 80.00, 95 percent CI 11.5 to 559; and intermediate activity OR 2.96, 95 percent CI 1.18 to 7.42), and homozygous and heterozygous TPMT variant allele genotype (OR 18.60, 95 percent CI 4.12 to 83.60; and 4.62, 95 percent CI 2.34 to 9.16, respectively). In general, TPMT phenotyping costs less than genotyping, although estimates across studies are quite heterogeneous. CONCLUSIONS: There is insufficient direct evidence regarding the effectiveness of pretesting of TPMT status in patients with chronic autoimmune diseases. Indirect evidence confirms strong association of leukopenia with lower levels of TPMT activity and carrier genotype already established in the literature.
MeSH:
Autoimmune Diseases/enzymology
Azathioprine/adverse effects
Azathioprine/therapeutic use
Evidence-Based Practice
Genetic Association Studies
Methyltransferases/genetics*
United States
Publication Type(s):
Meta-Analysis
Notes:
"Contract No. 290-2007-10059-I (EPCIII)."
""December 2010."
Includes bibliographical references.
Issued also in print.
Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, 540 Gaither Road, Rockville, MD 20850; www.ahrq.gov Contract Number: 290-2007-10059-I (EPCIII), Prepared by: University of Ottawa Evidence-based Practice Centre, Ottawa, ON, Canada.
Description based on online resourse; title from PDF title page (viewed on Feb. 13, 2012).
NLM ID:
101570723 [Electronic Resource]

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