Optimizing Azole Therapy in Chronic Pulmonary Aspergillosis: A Randomized Comparative Study of Itraconazole and Posaconazole Integrating Clinical Outcomes, Azole Exposure, and Resistance Surveillance

Chronic pulmonary aspergillosis (CPA) is a progressive fungal lung disease associated with substantial morbidity and mortality. India bears one of the largest global burdens of CPA owing to the high prevalence of post-tuberculosis lung disease (PTLD), the principal predisposing condition for CPA in low- and middle-income countries (Expert Rev Anti Infect Ther 2026;1-21; Mycoses 2025;68:e70060). Despite increasing recognition of CPA as a major public health problem, several critical gaps remain in the optimization of antifungal therapy, particularly with respect to azole selection, pharmacokinetic variability, and the emergence of antifungal resistance during prolonged treatment.

Oral itraconazole remains the recommended first-line therapy for CPA (Expert Rev Anti Infect Ther 2026;1-21; Mycoses 2025;68:e70060; Lancet Infect Dis 2026;26:239-249; Curr Opin Pulm Med 2024;30:156-166; Lancet Infect Dis 2022;22:1052-1061). Our group, in a randomized controlled trial, previously showed that extending itraconazole therapy from 6 to 12 months significantly improves treatment outcomes (Lancet Infect Dis 2022;22:1052-1061). However, itraconazole exhibits considerable inter-individual variability in systemic drug exposure, requires therapeutic drug monitoring, and may fail to achieve adequate systemic exposure in a subset of patients (J Antimicrob Chemother 2014;69:1162-1176). Furthermore, prolonged azole exposure may contribute to the development of antifungal resistance, an emerging challenge with important implications for long-term disease control (Expert Rev Anti Infect Ther 2026;1-21). More recently, we showed that voriconazole was not superior to itraconazole in treating CPA; moreover, it was associated with a higher incidence of adverse events (Lancet Infect Dis 2026;26:239-249).

Posaconazole is an attractive alternative to itraconazole and voriconazole owing to its favourable pharmacokinetic profile, predictable systemic exposure, improved tolerability, and potent activity against Aspergillus species. However, its role as primary therapy for CPA has not been evaluated in a randomized clinical trial (Expert Rev Anti Infect Ther 2026;1-21). In addition, prospective data on the emergence of azole resistance during prolonged therapy and its relationship with treatment outcomes remain limited.

This prospective, randomized, open-label comparative study will evaluate oral itraconazole and oral posaconazole in 220 treatment-naïve patients with CPA, with treatment for 12 months. The study will compare clinical effectiveness and safety of the study drugs.

By integrating clinical, microbiological, and azole exposure data, the proposed study seeks to identify determinants of treatment success and failure, define exposure-response relationships for azole therapy, and characterize the emergence of resistance during prolonged treatment. The findings will generate evidence to guide individualized antifungal therapy, inform antifungal stewardship strategies, and strengthen resistance surveillance frameworks for CPA. As the first randomized evaluation of posaconazole in CPA, the study has the potential to directly influence clinical practice and international treatment recommendations for this neglected fungal disease