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Cover of Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-Based Drugs

Assessment of Thiopurine Methyltransferase Activity in Patients Prescribed Azathioprine or Other Thiopurine-Based Drugs

Evidence Reports/Technology Assessments, No. 196

Investigators: , PhD, , MBBS, MMedSc, MPhil, , PhD, , PhD, , PhD, , MSc, , MLS, , PhD, , BHKin, , PhD, , MD, , MD, , BSc, DMM, , PhD, , BSc, , BA, , MD, MSc, and , MSc.

University of Ottawa Evidence-based Practice Centre
Rockville (MD): Agency for Healthcare Research and Quality (US); .
Report No.: 11-E002

Structured Abstract

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®, EMBASE®, and Healthstar were searched from inception to May 2010; the Cochrane Library® to October 2009; and BIOSIS®, 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.

Contents

540 Gaither Road, Rockville, MD 20850; www​.ahrq.gov

University of Ottawa EPC Director: David Moher, PhD

Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services1, Contract Number: 290-2007-10059-I (EPCIII), Prepared by: University of Ottawa Evidence-based Practice Centre, Ottawa, ON, Canada

Suggested citation:

Booth RA, Ansari MT, Tricco AC, Loit E, Weeks L, Doucette S, Skidmore B, Hoch JS, Tsouros S, Sears M, Sy R, Karsh J, Mani S, Galipeau J, Yurkiewich A, Daniel R, Tsertsvadze A, Yazdi F. Assessment of thiopurine methyltransferase activity in patients prescribed azathioprine or other thiopurine-based drugs. Evidence Report/Technology Assessment No. 196. (Prepared by the University of Ottawa Evidence-based Practice Center under Contract No. 290-2007-10059-I AHRQ Publication No. 11-E002. Rockville, MD: Agency for Healthcare Research and Quality. December 2010.

This report is based on research conducted by the University of Ottawa Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10059-I (EPCIII)). The findings and conclusions in this document are those of the author(s), who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

The information in this report is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This report is intended as a reference and not as a substitute for clinical judgment.

This report may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

No investigators have any affiliations or financial involvement (e.g., employment, consultancies, honoraria, stock options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented in this report.

1

540 Gaither Road, Rockville, MD 20850; www​.ahrq.gov

Bookshelf ID: NBK55935
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