Pharmacogenomic testing to prevent aminoglycoside-induced hearing loss in cystic fibrosis patients: potential impact on clinical, patient, and economic outcomes

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.