Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Lung Disease

BackgroundIn the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001).Research QuestionIn patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion?Study Design and MethodsAdults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation.ResultsMore patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment.InterpretationIn a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion.Trial RegistryClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001). In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment. In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov Nontuberculous mycobacteria (NTM) are a ubiquitous and diverse group of environmental organisms that vary in virulence and the ability to cause clinical disease in humans.1Falkinham III, J.O. Environmental sources of nontuberculous mycobacteria.Clin Chest Med. 2015; 36: 35-41Google Scholar In susceptible individuals, including those with underlying structural pulmonary disease, acquisition of NTM in the respiratory tract through inhalation of environmental aerosols can lead to chronic lung disease. Over an 8-year period in the United States, significant average annual increases in both the incidence (+5.2%; 95% CI, 4.0%-6.4%; P < .01) and prevalence (+7.5%; 95% CI, 6.7%-8.2%; P < .01) of NTM lung disease were reported, with Mycobacterium avium complex (MAC) identified as the leading cause of NTM lung disease in the United States and most regions of the world.2Prevots D.R. Marras T.K. Epidemiology of human pulmonary infection with nontuberculous mycobacteria: a review.Clin Chest Med. 2015; 36: 13-34Google Scholar,3Winthrop K.L. Marras T.K. Adjemian J. Zhang H. Wang P. Zhang Q. Incidence and prevalence of nontuberculous mycobacterial lung disease in a large U.S. managed care health plan, 2008-2015.Ann Am Thorac Soc. 2020; 17: 178-185Google Scholar The management of MAC lung disease can be challenging and complex.4Kwon Y.S. Koh W.J. Daley C.L. Treatment of Mycobacterium avium complex pulmonary disease.Tuberc Respir Dis (Seoul). 2019; 82: 15-26Google Scholar, 5Ryu Y.J. Koh W.J. Daley C.L. Diagnosis and treatment of nontuberculous mycobacterial lung disease: clinicians’ perspectives.Tuberc Respir Dis (Seoul). 2016; 79: 74-84Google Scholar, 6Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDS clinical practice guideline: executive summary.Clin Infect Dis. 2020; 71: e1-e36Google Scholar Treatment outcomes, which can vary by MAC species and the presence of antibiotic resistance or cavitary disease, often are poor.6Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDS clinical practice guideline: executive summary.Clin Infect Dis. 2020; 71: e1-e36Google Scholar,7Griffith D.E. Aksamit T.R. Therapy of refractory nontuberculous mycobacterial lung disease.Curr Opin Infect Dis. 2012; 25: 218-227Google Scholar Conversion of sputum culture results from positive to negative for MAC is the microbiological goal of therapy, with treatment success defined as 12 months of negative sputum culture results while receiving therapy.6Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDS clinical practice guideline: executive summary.Clin Infect Dis. 2020; 71: e1-e36Google Scholar,8Diel R. Nienhaus A. Ringshausen F.C. et al.Microbiologic outcome of interventions against Mycobacterium avium complex pulmonary disease: a systematic review.Chest. 2018; 153: 888-921Google Scholar,9Griffith D.E. Aksamit T. Brown-Elliott B.A. et al.An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Google Scholar Failure to achieve culture conversion or the emergence of microbiologic recurrence of the same MAC strain while receiving treatment (relapse) are common, despite lengthy treatment with a guideline-based multidrug regimen.6Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDS clinical practice guideline: executive summary.Clin Infect Dis. 2020; 71: e1-e36Google Scholar,8Diel R. Nienhaus A. Ringshausen F.C. et al.Microbiologic outcome of interventions against Mycobacterium avium complex pulmonary disease: a systematic review.Chest. 2018; 153: 888-921Google Scholar,10Johnson M.M. Odell J.A. Nontuberculous mycobacterial pulmonary infections.J Thorac Dis. 2014; 6: 210-220Google Scholar,11van Ingen J. Aksamit T. Andrejak C. et al.Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement.Eur Respir J. 2018; 51: Scholar with treatment the for that most patients are to infection often environmental to T. sources of a mycobacterial Mycobacterium avium Brown-Elliott B.A. et therapy for Mycobacterium avium complex lung 2014; Scholar liposome inhalation suspension was for to amikacin while the of P. et and in of amikacin in chronic lung infections.J J. et liposome inhalation suspension (ALIS) mycobacterial and amikacin 2018; Scholar In the 3 CONVERT study, ALIS added to guideline-based treatment (GBT) in patients with refractory MAC lung disease met the primary end point of increased of culture conversion by 6 months of for ALIS plus GBT vs 8.9% for GBT P < D.E. 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R. et in and sputum culture conversion with amikacin liposome inhalation suspension (ALIS) for treatment of refractory Mycobacterium avium complex (MAC) lung disease 2018; Scholar The of of ALIS in patients with treatment-refractory lung disease by MAC in a primary D.E. R. et liposome inhalation suspension for treatment-refractory lung disease by Mycobacterium avium complex a randomized J Respir Crit Care Med. 2018; Scholar patients were with MAC lung D.E. Aksamit T. Brown-Elliott B.A. et al.An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175: 367-416Google Scholar and sputum results within 6 months of and despite treatment with GBT of for 6 the for CONVERT D.E. 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