Mycobacterium avium complex pulmonary disease patients with limited treatment options

Extract Over recent decades, the prevalence and incidence of nontuberculous mycobacterial pulmonary disease (NTM-PD) have increased worldwide, with Mycobacterium avium complex being the most common causative agents [1–5]. The 2020 American Thoracic Society/European Respiratory Society/European Society of Clinical Microbiology and Infectious Diseases/Infectious Diseases Society of America (ATS/ERS/ESCMID/IDSA) guidelines recommended a treatment regimen with at least three drugs, including a macrolide, in patients with a nodular–bronchiectatic, macrolide-susceptible M. avium complex pulmonary disease (MAC-PD) [6].

clinical situations personally confronted by the panel experts followed, with the development of a draft set of real-life cases of possible MAC-PD patients with LTOs from those real-life cases.Before the Consensus Conference, the panel experts voted blindly online to decide if they considered the cases as LTO situations with the following voting options: "Yes, an LTO example", "No, not an LTO example" and "Not enough information to decide".Draft examples without full expert endorsement were either modified or discarded.During the face-to-face meeting in Milan, the experts discussed and altered the iconic illustrations and their descriptors ("statements") to reach a consensus about their relevance as realistic clinical possibilities.As a final step, the panel members voted on each statement using a modified Delphi method.The double goals of the voting process, with scores variable from 0 to 10, were to confirm whether each iconic statement might qualify as an actual MAC-PD LTO and whether ALIS might have a role in the real-life management of such situations.
All experts considered refractory MAC-PD (according to the 2020 ATS/ERS/ESCMID/IDSA guidelines definition) as an LTO situation (100% agreement), including both smear-negative and smear-positive disease, and to include ALIS in their treatment strategy.Some experts would also consider using intravenous amikacin in some refractory conditions with evidence of continuing severe disease.In smear-positive, nodular-bronchiectatic, refractory MAC-PD, two experts would start i.v.amikacin before shifting to ALIS.In cavitary refractory MAC-PD, one expert would start i.v.amikacin before turning to ALIS.The FDA license and the clinical guidelines based on the evidence provided by the CONVERT study cover refractory MAC-PD.However, given the wording of the EMA licensing, the expert panel identified seven potential LTOs for MAC-PD patients (table 1).The panel also debated whether the now available ALIS formulation could be speculatively used with benefit in each of these situations while unanimously acknowledging that current evidence is for refractory MAC-PD only.At any rate, all the described speculative scenarios cannot and should not be equated to the EMA's definition of LTOs.Confirmatory validation through targeted clinical trials would still be a must.All 14 voting members of the panel agreed that newly diagnosed, noncavitary MAC-PD caused by a macrolide-resistant strain represents an LTO, regardless of whether the strain is amikacin-susceptible or amikacin-intermediate [13].All experts agreed that some patients might derive potential benefits from ALIS in this group, although with the understanding that there is no direct evidence for the benefit of ALIS in this specific setting.The experts also recognised newly diagnosed MAC-PD caused by a Regarding MAC-PD patients intolerant of a GBT regimen for any reason, the outcomes of discussions were variable.If feasible, switching within the macrolide class should consistently preserve a macrolide-based regimen.Premature discontinuation of the macrolide because of an inability to take the drug was considered an LTO situation by all the experts, who also unanimously (100%) identified a potential role of ALIS in this case.Some experts also argue about initiating i.v.amikacin according to the patient's preferences or needs.The inability to take ethambutol was also recognised as an LTO situation, with most experts not identifying any role for the ALIS formulation (11 out of 14 voting panel members, 79% ).An oral drug, such as clofazimine, seemed advisable in cases of intolerance to the "companion" drug ethambutol [6].Intolerance of rifamycins was regarded as an LTO situation by only three experts out of 14 (21%), with emerging data and ongoing clinical trials (www.clinicaltrials.govidentifier numbers NCT03672630 and NCTO4677569) investigating their concrete benefit in MAC-PD patients [16].In these cases, the advice was to try switching within the rifamycin class or considering clofazimine as a third drug with no role for ALIS.Finally, when suggested by guidelines (e.g.cavitary disease), the inability to use i.v.amikacin was also considered an LTO situation by all the experts who unanimously (100%) agreed that ALIS administration could be an option in this case.
Relapses in a GBT-treated patient were the final situation discussed, unanimously (100%) recognised as LTO conditions with a role for the proprietary ALIS formulation for all experts.Provided there was adequate compliance to GBT, drug susceptibility testing and the frequency of microbiology work-up are essential when deciding on treatment.It is crucial to try differentiating relapse from re-infection by genome sequencing, with relapse considered similar to a refractory situation.All experts agreed that re-infections are not an LTO situation.
This expert panel discussion and consensus might help physicians interpret EMA documents referring to LTO in MAC-PD patients.However, it is essential to understand that the value of the document is in discussing which conditions may relate to MAC-PD patients with LTO and in which of these the panel considers that there could be some potential benefit of using ALIS with the knowledge that, at present, evidence and guidelines on the use of ALIS relate to refractory MAC-PD.

TABLE 1
[6,14,15]resistant strain as an LTO situation.The 2018 Clinical and Laboratory Standards Institute M24-A3 and M62 guidelines and the ATS/ERS NTM guideline laboratory section support the use of ALIS with i.v.amikacin-resistant strains if the amikacin minimum inhibitory concentration (MIC) is 64 µg•mL −1 associated with i.v.amikacin resistance and ALIS susceptibility, due to high local concentrations and potentially improved intracellular penetration of the liposomal formulation[6,14,15].All experts agreed that the proprietary ALIS formulation should not be an option if amikacin MICs are ⩾128 µg•mL −1 .Seven experts (50%) acknowledged the role of ALIS in the macrolide-resistant, amikacin-resistant (>64 and <128 µg•mL −1 ) strain condition.
1,2, Francesco Blasi3,4, Pierre-Régis Burgel5,6, Andrea Calcagno7, Andreas Fløe 8 , Dorothy Grogono 9 , Apostolos Papavasileiou 10 , Eva Polverino11, Concepción Prados12, Gernot Rohde 13 , Helmut J.F. Salzer14,15,16, Adrián Sánchez-Montalvá17,18,19, Michal Shteinberg20, Eva Van Braeckel21,22, Jakko van Ingen 23 , Nicolas Veziris 24 , Dirk Wagner 25 and Michael R. Loebinger 26 grants or contracts from Insmed, outside the submitted work; consulting fees from Insmed, outside the submitted work; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Insmed, outside the submitted work.E. Van Braeckel is Chair of the Belgian Respiratory Society working group on respiratory infections, unpaid, outside the submitted work.J. van Ingen reports grants or contracts from MannKind and AN2, outside the submitted work; patents planned, issued or pending: Inhaled tigecycline for M. abscessus treatment, outside the submitted work.N. Veziris reports receiving support for the present manuscript from Insmed; grants or contracts from Bioversys, outside the submitted work; consulting fees from Insmed and Becton Dickinson, outside the submitted work; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Insmed, outside the submitted work; payment for expert testimony from Insmed, outside the submitted work; support for attending meetings and/or travel from Insmed, outside the submitted work; and was involved in the Respiri-NTM consortium with Janssen, outside the submitted work.D. Wagner reports support for the present manuscript from Publi Creations SAM via an unrestricted grant by Insmed Inc.; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Biomerieux, outside the submitted work; participation on a Data Safety Monitoring Board or Advisory Board for Pfizer, outside the submitted work; and participation in clinical trials for Insmed, outside the submitted work.S. Aliberti reports grants or contracts from Insmed Incorporated, Chiesi, Fisher & Paykel and GSK, outside the submitted work; royalties or licences from McGraw Hill, outside the submitted work; consulting fees from Insmed Incorporated, Insmed Italy, Insmed Ireland Ltd, Zambon Spa, AstraZeneca UK Limited, AstraZeneca Pharmaceutical LP, CSL Behring GmbH, Grifols, Fondazione Internazionale Menarini, Moderna, Chiesi, MSD Italia S.r.l., Brahms, Physioassist SAS and GlaxoSmithKline Spa, outside the submitted work; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from GlaxoSmithKline Spa, Thermofisher Scientific, Insmed Italy, Insmed Ireland Ltd, Zambon, and Fondazione Internazionale Menarini, outside the submitted work; participation on a Data Safety Monitoring Board or Advisory Board for INSMED Incorporated, INSMED Italy, AstraZeneca UK Limited, and MSD Italia S.r.l, outside the submitted work.F. Blasi reports grants or contracts from AstraZeneca, Chiesi, GlaxoSmithKline and Insmed, outside the submitted work; consulting fees from GlaxoSmithKline, Menarini and OM Pharma, outside the submitted work; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from AstraZeneca, Chiesi, GlaxoSmithKline, Grifols, Insmed, Menarini, Novartis, OM Pharma, Pfizer, Sanofi, Vertex, Viatris and Zambon, outside the submitted work.A. Papavasileiou reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Insmed, outside the submitted work.M.R. Loebinger reports consulting fees from Armata, 30T, AstraZeneca, Parion, Insmed, Chiesi, Zambon, Electromed, Recode, AN2, Savara, Boehringer Ingelheim and Mannkind, outside the submitted work; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Insmed, outside the submitted work; and is chair of the ERS Respiratory Infection group, outside the submitted work.D. Grogono reports consulting fees from Insmed, outside the submitted work; and support received from Insmed for attending a consensus meeting.C. Prados has nothing to disclose.Support statement: The consensus conference activities, born of acknowledgement by participating experts of possible undefined points in current regulatory definitions of pulmonary disease due to Mycobacterium avium complex, benefited from an unrestricted grant from INSMED Netherlands B.V.