title: Pharmacogenomic testing to prevent aminoglycoside-induced hearing loss in cystic fibrosis patients: potential impact on clinical, patient, and economic outcomes.
abstract: BACKGROUND
  Aminoglycosides are commonly used in cystic fibrosis patients to treat Pseudomonas aeruginosa respiratory infections. Aminoglycoside-induced hearing loss may occur in 1%-15% of patients with cystic fibrosis, ranging from mild to severe. Recently, a genetic test to identify patients with a mitochondrial mutation (A1555G) that may predispose patients to this adverse event has become available. Although the A1555G variant is very rare, it seems to confer a high risk of severe hearing loss in patients exposed to aminoglycosides.
  
  
  OBJECTIVE
  The objective was to evaluate the potential clinical, patient, and economic outcomes associated with the use of A1555G testing in a cystic fibrosis population, and explore data gaps and uncertainty in its clinical implementation.
  
  
  METHODS
  We developed a decision-analytic model to evaluate a hypothetical cohort of patients with cystic fibrosis from a societal perspective. Clinical and economic data were derived primarily from a critical literature review. The incidence of aminoglycoside-induced severe hearing loss, quality-adjusted life-years, and total health care costs were evaluated. Sensitivity analyses were conducted to evaluate uncertainty in our results.
  
  
  RESULTS
  In the base-case analysis, A1555G testing decreased the risk of severe aminoglycoside-induced hearing loss by 0.12% in the cystic fibrosis population. The discounted incremental cost per quality-adjusted life-years gained was $79,300, but varied widely from $33,000 to testing being dominated by the no testing strategy (higher costs and lower quality-adjusted life-years with testing) in sensitivity analyses. If avoidance of aminoglycosides in patients testing positive leads to an absolute increase in the lifetime risk of death from Pseudomonas infection of 0.8% or greater, A1555G testing would lead to a decrease in quality-adjusted life-years.
  
  
  CONCLUSIONS
  The results of our analysis suggest that there are significant data gaps and uncertainty in the outcomes with A1555G testing, but it is not likely cost-effective, and could lead to worse patient outcomes due to avoidance of first-line therapy in the >95% of patients who are false-positives. Additional research is needed before pharmacogenetic testing for the A1555G mitochondrial mutation can be recommended, even in a population with a high likelihood of exposure to aminoglycosides.
authors: Institute for Public Health Genetics, Department of Pharmacy, University of Washington, Seattle, Washington 98195, USA. veenstra@u.washington.edu
authors: David L
authors: DL
authors: Veenstra
authors: Julie
authors: J
authors: Harris
authors: Ronald L
authors: RL
authors: Gibson
authors: Margaret
authors: M
authors: Rosenfeld
authors: Wylie
authors: W
authors: Burke
authors: Carolyn
authors: C
authors: Watts
mesh_terms: D000293:Adolescent; D000328:Adult; D000617:Aminoglycosides / Q000009:adverse effects*; D000900:Anti-Bacterial Agents / Q000009:adverse effects*; D002648:Child; D015331:Cohort Studies; D003362:Cost-Benefit Analysis; D003550:Cystic Fibrosis / Q000150:complications* / Q000191:economics; D020022:Genetic Predisposition to Disease; D034381:Hearing Loss / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D009154:Mutation; D017063:Outcome Assessment, Health Care; D010597:Pharmacogenetics; D019057:Quality-Adjusted Life Years
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents