Objectives

Tobacco smoke exposure reduces CFTR functional expression in vitro and contributes to acquired CFTR dysfunction. We investigated whether it also inhibits the clinical benefit of CFTR modulators, focusing on tezacaftor/ivacaftor, approved in February 2018 for individuals with CF age ≥12 years.

Methods

A retrospective longitudinal analysis of encounter-based data from the CF Foundation Patient Registry (2016–2018) compared the slope of change in lung function (GLI FEV₁% predicted) before and after tezacaftor/ivacaftor initiation in smoke-exposed vs unexposed age-eligible pediatric patients. Tobacco smoke exposure (Ever/Never) was determined from caregiver self-report. Statistical analyses used hierarchical linear mixed modeling and fixed effects regression modeling.

Results

The sample included 6,653 individuals with a total of 105,539 person-period observations. Tezacaftor/ivacaftor was prescribed to 19% (1,251) of individuals, mean age 17 years, mean baseline ppFEV₁ 83%, 28% smoke-exposed. Tezacaftor/ivacaftor users who were smoke-exposed had a lower baseline ppFEV₁ and experienced a greater lung function decline. Over two years, the difference in ppFEV₁ by smoke exposure among tezacaftor/ivacaftor users increased by 1.2% (7.6% to 8.8%, p<0.001). In both mixed effects and fixed effects regression models, tezacaftor/ivacaftor use was associated with improved ppFEV₁ among unexposed individuals (1.2% and 1.7%, respectively; p<0.001 for both) but provided no benefit among smoke-exposed counterparts (0.3%, p = 0.5 and 0.6%, p = 0.07, respectively).

Conclusion

Tobacco smoke exposure nullifies the therapeutic benefit of tezacaftor/ivacaftor among individuals with CF aged 12–20 years old. To maximize the therapeutic opportunity of CFTR modulators, every effort must be taken to eliminate smoke exposure in CF.

中文翻译：

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烟草烟雾暴露限制了 tezacaftor/ivacaftor 在小儿囊性纤维化患者中的治疗益处

目标

烟草烟雾暴露会降低体外 CFTR 功能表达并导致获得性 CFTR 功能障碍。我们调查了它是否也抑制了 CFTR 调节剂的临床益处，重点是 tezacaftor/ivacaftor，于 2018 年 2 月批准用于 CF 年龄≥12 岁的个体。

方法

对来自 CF 基金会患者登记处（2016-2018 年）的基于遭遇的数据进行的回顾性纵向分析比较了tezacaftor/ivacaftor 在烟雾暴露与未暴露年龄之间的肺功能变化斜率（GLI FEV ₁ % 预测）符合条件的儿科患者。烟草烟雾暴露（曾经/从不）是根据照顾者的自我报告确定的。统计分析使用分层线性混合模型和固定效应回归模型。

结果

样本包括 6,653 个人，共有 105,539 个人期观察。Tezacaftor/ivacaftor 被处方给 19% (1,251) 的个体，平均年龄 17 岁，平均基线 ppFEV ₁ 83%，28% 暴露于烟雾。暴露于烟雾的 Tezacaftor/ivacaftor 使用者基线 ppFEV ₁较低，肺功能下降幅度更大。两年多来，tezacaftor/ivacaftor 使用者的烟雾暴露导致的 ppFEV ₁差异增加了 1.2%（7.6% 至 8.8%，p <0.001）。在混合效应和固定效应回归模型中，tezacaftor/ivacaftor 的使用与未暴露个体的 ppFEV ₁改善相关（分别为 1.2% 和 1.7%；p两者均<0.001），但在暴露于烟雾的同行中没有任何益处（分别为0.3%，p  = 0.5和0.6%，p  = 0.07）。

结论

烟草烟雾暴露使 tezacaftor/ivacaftor 对 12-20 岁 CF 患者的治疗益处无效。为了最大限度地利用 CFTR 调节剂的治疗机会，必须尽一切努力消除 CF 中的烟雾暴露。