Veenstra David L, Harris Julie, Gibson Ronald L, Rosenfeld Margaret, Burke Wylie, Watts Carolyn
Institute for Public Health Genetics, Department of Pharmacy, University of Washington, Seattle, Washington 98195, USA.
Genet Med. 2007 Oct;9(10):695-704. doi: 10.1097/gim.0b013e318156dd07.
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.
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.
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.
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.
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.
氨基糖苷类药物常用于囊性纤维化患者，以治疗铜绿假单胞菌引起的呼吸道感染。在1% - 15%的囊性纤维化患者中可能会发生氨基糖苷类药物导致的听力损失，程度从轻度到重度不等。最近，一种基因检测方法可用于识别携带线粒体突变（A1555G）的患者，这种突变可能使患者易发生这一不良事件。尽管A1555G变异非常罕见，但在接触氨基糖苷类药物的患者中，它似乎会带来严重听力损失的高风险。
目的是评估在囊性纤维化人群中使用A1555G检测相关的潜在临床、患者和经济结局，并探讨其临床应用中的数据空白和不确定性。
我们建立了一个决策分析模型，从社会角度评估一组假设的囊性纤维化患者。临床和经济数据主要来自严格的文献综述。评估了氨基糖苷类药物导致的严重听力损失的发生率、质量调整生命年和总医疗费用。进行敏感性分析以评估结果的不确定性。
在基础病例分析中，A1555G检测使囊性纤维化人群中氨基糖苷类药物导致的严重听力损失风险降低了0.12%。每获得一个质量调整生命年的贴现增量成本为79,300美元，但在敏感性分析中差异很大，从33,000美元到检测被不检测策略主导（检测成本更高且质量调整生命年更低）。如果对检测呈阳性的患者避免使用氨基糖苷类药物导致因铜绿假单胞菌感染而死亡的终身风险绝对增加0.8%或更高，A1555G检测将导致质量调整生命年减少。
我们的分析结果表明，A1555G检测的结局存在显著的数据空白和不确定性，但它不太可能具有成本效益，并且由于在95%以上的假阳性患者中避免一线治疗，可能导致患者结局更差。在推荐对A1555G线粒体突变进行药物遗传学检测之前，即使在极有可能接触氨基糖苷类药物的人群中，也需要进行更多研究。
