Nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex - disease burden, unmet needs, and advances in treatment developments

Figures & data

Figure 1. NTM Pathogenesis and Dysfunction of the Phagosome

Source: Illustration based on Busatto et al. 2019 [9] and Shu et al. 2020 [138]

^aT helper 1 cell immunity has been suggested as a major protective mechanism against NTM intracellular infection. Diseases and therapies that reduce cell-mediated immunity increase risk of NTM-LD.

GPL = glycopeptidolipid; NTM (-LD) = nontuberculous mycobacteria (lung disease); TLRs = toll-like receptors

Figure 2. SF-36 Scores in Patients with NTM-LD Compared with Population Norms in Canada*

Source: Mehta and Marras 2011 [48]

* P < 0.001 for all comparison; higher scores indicate better quality of life

NTM-LD = nontuberculous mycobacterial lung disease; SF-36 = 36-item Short Form Health Survey

Table 1. Mortality Estimates Among Patients with NTM-LD Compared with Matched Controls

Country, Source	Period/population	Results
US Mourad, 2021 [57]	Diagnosed with NTM-LD between 1996 and 2015 Retrospective cohort; university health system	All-cause mortality 5 years after diagnosis was 44.9% (95% CI, 38.0–51.1) among patients with NTM-LD and comorbidities and 25.0% (95% CI, 19.5–30.1) among those without comorbidities, compared with 5.7% in a demographically matched general population cohort
US Adjemian, 2012 [139]	1997 to 2007 Medicare beneficiaries	Patients with NTM-LD were 40% more likely to die over the study period vs matched controls (OR = 1.4; 95% CI, 1.3–1.6)
US Marras, 2018 [56]	Between 2007 and 2016 US national managed care insurance plan	Multivariable adjusted Cox regression showed the risk of all-cause mortality was doubled in patients with NTM-LD vs matched controls (HR = 2.06; 95% CI, 1.52–2.79; P < 0.001)
Canada Marras, 2017 [55]	2001 to 2013 Ontario population	1- and 5-year all-cause mortality rates were increased for patients with MAC-LD vs matched controls (HR = 1.57; 95% CI, 1.48–1.66)
Germany Diel, 2017 [54]	2010 to 2011 Representative sample of the German population	Patients with NTM-LD had a nearly 4-fold higher risk of death vs matched controls over a 39-month follow-up period (HR = 3.64; 95% CI, 2.28–5.77; P < 0.0001)
South Korea Park, 2019 [52]	Between 2005 and 2008 Representative sample of the South Korean population	All-cause mortality risk in patients with progressive NTM-LD (N = 355) compared with no NTM-LD group (N = 16,453,739) was over 3-times higher (HR = 3.248; 95% CI, 2.433–4.336)

HR = hazard ratio; MAC-LD = Mycobacterium avium complex lung disease; NTM-LD = nontuberculous mycobacterial lung disease; OR = odds ratio; US = United States

Table 2. Key Outcomes for Management of NTM-LD, per the NTM-NET Consensus

Outcome	Definition
Culture conversion	The finding of ≥ 3 consecutive negative mycobacterial cultures from respiratory samples, collected ≥ 4 weeks apart, during antimycobacterial treatment (the sampling date of the first negative culture is then the date of culture conversion)
Microbiological cure	Finding multiple consecutive negative but no positive cultures with the causative species from respiratory samples after culture conversion and until the end of antimycobacterial treatment
Clinical cure	Patient-reported and/or objective improvement of symptoms during antimycobacterial treatment, sustained until at least the end of treatment, but no cultures available to prove culture conversion or microbiological cure
Cure	Antimycobacterial treatment completed, with fulfillment of criteria for both microbiological and clinical cure
Treatment failure	The reemergence of multiple positive cultures or persistence of positive cultures with the causative species from respiratory samples after ≥ 12 months of antimycobacterial treatment, while the patient is still on treatment
Recurrence	The reemergence of at least 2 positive cultures with the causative species from respiratory samples after cessation of antimycobacterial treatment
Relapse	The emergence of at least 2 positive cultures with the same strain of the causative species after the end of treatment
Reinfection	The emergence of at least 2 positive cultures with a different strain of the causative species or a strain of a different species after the initiation of the treatment episode

Source: van Ingen et al. 2018 [66]

Adapted with permission of the © ERS 2021: European Respiratory Journal 2018 51: 1800170; DOI: 10.1183/13993003.00170–2018

NTM-LD = nontuberculous mycobacterial lung disease; NTM-NET = Nontuberculous Mycobacteria Network European Trials Group

Table 3. 2020 ATS/ERS/ESCMID/IDSA Recommended Treatment Regimens^a for MAC-LD According to Disease Status and/or Severity

Disease Type
Nodular/bronchiectatic	Cavitary	Refractory^c
Azithromycin 500 mg TIW (or clarithromycin 1000 mg TIW) Rifampicin 600 mg TIW (or rifabutin 300 mg TIW) Ethambutol 25 mg/kg TIW	Azithromycin 250–500 mg daily (or clarithromycin 1000 mg daily) Rifampicin 450 or 600 mg daily (or rifabutin 150–300 mg daily) Ethambutol 15 mg/kg daily IV amikacin^b 10–15 mg/kg daily or 15–25 mg/kg TIW (or IV streptomycin^b 10–15 mg/kg daily or 15–25 mg/kg TIW)	Azithromycin 250–500 mg daily (or clarithromycin 1000 mg daily) Rifampicin 450 or 600 mg daily (or rifabutin 150–300 mg daily) Ethambutol 15 mg/kg daily ALIS 590 mg daily (strong recommendation) or, if cavitary/severe disease is present, IV amikacin^b 10–15 mg/kg daily or 15–25 mg/kg TIW (or IV streptomycin^b 10–15 mg/kg daily or 15–25 mg/kg TIW)

Source: Daley et al. 2020 [1]

^aFor patients who are intolerant of or whose isolate is resistant to first-line drugs, alternate drugs include clofazimine, moxifloxacin, and linezolid, and some experts would consider bedaquiline or tedizolid. ^b Consider for cavitary, extensive nodular/bronchiectatic disease, or macrolide-resistant MAC. Amikacin or streptomycin may be given TIW. ^c Definition of refractory disease is ‘remaining sputum culture positive after 6 months of GBT’. ALIS when added to GBT has been shown to improve culture conversion in patients with refractory MAC-LD.

ALIS = amikacin liposome inhalation suspension; ATS = American Thoracic Society; ERS = European Respiratory Society; ESCMID = European Society of Clinical Microbiology and Infectious Diseases; GBT = guideline-based therapy; IDSA = Infectious Disease Society of America; IV = intravenous; MAC-LD = Mycobacterium avium complex lung disease; TIW = 3 times weekly

Figure 3. Depiction of Amikacin Liposome Inhalation Suspension (ALIS) Liposome Structure Source: Amikacin liposomal inhalation suspension [package insert] 2020 [97]

Figure 4. Culture Conversion at 6 months, and Sustainability and Durability of Culture Conversion Among Patients Who Completed a Full 12 Months of Post-conversion Treatment in the CONVERT Study

Source: Griffith et al. 2021 [109], Griffith et al. 2018 [67]

ALIS = amikacin liposome inhalation suspension; EOT = end of treatment

Note: Patients at the End of Treatment and 3 months off treatment assessments were classified as either culture negative or culture positive; patients who did not have sputum culture results available were therefore considered ‘culture positive’.

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