Assessment of posaconazole salvage therapy in chronic pulmonary aspergillosis using predefined response criteria

Highlights

• Chronic pulmonary aspergillosis is a chronic, symptomatic and potentially fatal disease.

• Posaconazole has shown to be a good alternative to first-line therapy in patients with CPA but its use may be limited by side effects and cost.

• Establishing pre-set targets for therapeutic success offered a clear, safe and sustainable method of identifying patients who benefited from posaconazole therapy, and minimized continuation of ineffective therapy in those who did not.

ABSTRACT

Objectives

Chronic pulmonary aspergillosis (CPA) is a progressive infection that destroys lung tissue in non-immunocompromised patients. First-line therapies for CPA (itraconazole and/or voriconazole) are often curtailed due to toxicity or the development of drug resistance. Posaconazole is a potential alternative for these patients.

Methods

Use of posaconazole was funded by the National Health Service Highly Specialised National Commissioners on an individual basis for patients who failed or did not tolerate first-line therapy; those who met predefined criteria for improvement at 4 and 6 months (weight gain and/or improvement in St George's Respiratory Questionnaire) continued posaconazole long-term. We recorded response, failure, discontinuation rates, and adverse events.

Results

Seventy-eight patients received posaconazole as salvage therapy. Thirty-four (44%) achieved targets for continuation of therapy. Fourteen (18%) failed therapy; five (36%) patients did not achieve clinical targets at 4 or 6 months of assessment and nine (64%) developed clinical and/or radiological failure. Twenty-eight (36%) discontinued their trial early; 8 (29%) died and 20 (71%) had significant side effects. One patient was non-compliant and another was lost to follow up.

Conclusions

Establishing criteria for therapeutic success offered a clear, safe and sustainable method of identifying patients who benefit from additional therapy, and minimised continuation of ineffective therapy in those who did not.

Introduction

Chronic pulmonary aspergillosis (CPA) is a slowly progressive infection mainly caused by Aspergillus fumigatus, characterized by inflammatory destruction of lung tissue with cavitation, pleural thickening and/or fibrosis, and associated with significant respiratory and constitutional symptoms [1], [2], [3]. CPA usually affects patients with underlying structural airway disease with air-filled cavities or bullae, such as tuberculosis (TB), non-tuberculous mycobacterial infection, chronic obstructive pulmonary disease (COPD), allergic bronchopulmonary aspergillosis (ABPA), pneumothorax and sarcoidosis. This entity is associated with significant morbidity and mortality [4], [5], [6], [7]. In a recent large retrospective analysis of 387 CPA patients, survival at 1, 5 and 10 years from first visit was 86%, 62% and 47%, respectively [8]. Worse outcomes were associated with nontuberculous mycobacteria co-infection, COPD, pleural involvement, bilateral cavitary disease or aspergillomas, low body mass and low albumin.

Long-term treatment of CPA has been shown to improve symptoms and patients’ functional status, prevent the progressive destruction of lung tissue and the development of pulmonary fibrosis, and reduce death rates and morbidity [5], [9]. However, treatment is often long-term or lifelong and may be limited by intolerable side effects or the emergence of resistance [10]. Tri-azole antifungal agents, such as itraconazole and voriconazole, are the standard therapy recommended for CPA [9], [11], [12], [13], [14], [15], [16]. Posaconazole is a broad-spectrum tri-azole agent with potent activity against Aspergillus species. This agent has been shown to be a good alternative for patients with CPA [17] but, as with other azole therapies, its use can be limited due to side effects, interactions and high cost. Additionally, all current data on the use of posaconazole in CPA are retrospective.

Assessing response to therapy in CPA is problematic, as patients may suffer from concomitant bacterial or mycobacterial infection, or from deterioration of underlying disease such as COPD or sarcoidosis. Most series on azole therapy for CPA show response rates between 44% and 80% [9], [11], [12], [13], [14], [17], although criteria for response are not well characterised. Most of the studies include subjective and objective endpoints such as clinical, radiological, serological and microbiological criteria. Radiological improvement, the most objective criterion, is not always seen, in our experience, even if clinical improvement is evident. Use of quality-of-life (QoL) questionnaires such as the St George's Respiratory Questionnaire (SGRQ) has been validated in CPA and shown to correlate with clinical improvement [18]. Therefore, use of this questionnaire could be a way of determining which patients might benefit from long-term treatment with posaconazole, thereby limiting cost and toxicity by stopping a high-cost drug in patients who are unlikely to benefit.

The aim of this study is to assess whether pre-set targets of improvement in SGRQ and weight gain can be used as criteria of response to posaconazole therapy in CPA, in order to determine which patients respond to therapy, rather than denying treatment to all on the basis of cost and limited efficacy data.