Abstract
Background
Clofazimine is increasingly recommended for nontuberculous mycobacterial (NTM) infections, despite limited evidence. In Belgium, until July 2025 access to clofazimine - outside of procurement by the national tuberculosis program - was restricted and associated with financial and administrative hurdles, creating barriers for patients.
Methods
This retrospective, multicentre study documents clofazimine use from January 2015 to December 2024 through pharmacy and medical record review at Belgium’s two largest tertiary care hospitals. Collected data included indications, treatment duration, adverse events and logistic aspects related to access. Data was summarized using descriptive statistics.
Results
Among 102 clofazimine-containing treatment courses for NTM disease (61 in UZ Leuven; 41 in UZ Gent), the median patient age was 62 years; 52% were female, 56% had bronchiectasis, 28% COPD and 12% cystic fibrosis. Clofazimine was mainly used for NTM-pulmonary disease (NTM-PD) (n = 82, 87.2%), with main indications being M. abscessus complex-PD (MAB-PD; 28%), advanced or refractory M. avium complex-PD (MAC-PD; 17% and 12.2% respectively) or intolerance to another key drug (26.8%). Clofazimine was part of at least a triple-drug regimen, with 100 mg daily used in 91% of regimens for a median duration of 270 days (IQR 109–527 days). Common adverse events included ichthyosis/skin hyperpigmentation (38.3%) and gastrointestinal complaints (52.1%). Although none were severe, 20% of patients discontinued treatment prematurely. Financial reimbursement requests were submitted for 68.2% of NTM-PD treatments.
Conclusion
Our study observed that clofazimine is prescribed largely in accordance with current guideline recommendations. Given its acceptable tolerability and the recent introduction of national health insurance coverage, clofazimine use is likely to increase in Belgium, with the potential to improve patient outcomes.
Trial registration
This study did not involve a health care intervention and did not meet criteria for clinical trial registration. It was conducted as a retrospective, multicentre study at UZ Leuven and UZ Gent. Ethical approval was obtained from the Ethics Committee of UZ/KU Leuven (MP034837, S70431) and the Ethics Committee of UZ Gent (S61188, S62926). Clinical trial number: not applicable.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12890-026-04461-2.
Keywords: Clofazimine, Nontuberculous mycobacteria, Mycobacterium abscessus complex, Mycobacterium avium complex, Pulmonary disease, Drug access, Adverse events.
Background
Nontuberculous mycobacteria (NTM), which comprise all mycobacterial species other than Mycobacterium tuberculosis complex and Mycobacterium leprae complex, are ubiquitous environmental organisms. Approximately 200 species have been identified to date, but only a small proportion is of clinical significance in humans. Nontuberculous mycobacterial pulmonary disease (NTM-PD) is the most common clinical presentation, primarily affecting individuals with underlying lung diseases such as bronchiectasis and chronic obstructive pulmonary disease (COPD), or those with an immunodeficiency [1]. While the species distribution and the incidence of NTM-PD vary geographically, it has become an increasingly significant global health concern due to its rising prevalence and incidence [2–4].
NTM-PD proves difficult to treat, but if left untreated, might have a substantial impact on patient morbidity and mortality [1, 5, 6]. Treatment goals vary from pursuing microbiological eradication to improving symptoms and preventing radiological disease progression. Specific treatment regimens on the four most clinically relevant species are recommended in the 2020 joint clinical practice guideline by the American Thoracic Society (ATS), the European Respiratory Society (ERS), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the Infectious Diseases Society of America (IDSA). The treatment of NTM-PD presents multiple challenges, primarily due to the species-specific treatment regimens, accounting for intrinsic and acquired resistance, requiring multiple antimicrobial agents that are often associated with significant adverse events. Furthermore, therapy must be continued for extended periods, often up to twelve months after culture conversion [1, 7]. Despite prolonged treatment, a high level of treatment failure has been reported in previous studies, with only 61–66% of sustained culture conversion in M. avium complex pulmonary disease (MAC-PD) despite the guideline-based regimens and even lower success rates in M. abscessus complex pulmonary disease (MAB-PD) [8].
Clofazimine, an old riminophenazine, has a broad range of antimycobacterial activity; it is part of treatment regimens against M. leprae, drug-resistant M. tuberculosis, and more recently also NTM disease [9]. Although the evidence is rather limited, the drug features in all international guidelines for NTM management, where it is considered standard of care in MAB-PD or in macrolide-resistant MAC-PD, and a substitute for ethambutol or rifampicin in case of intolerance [6, 7]. As treatment indications for complex conditions such as NTM disease have been increasing over the past years, also the need for clofazimine has been rising. However, expertise in clofazimine use is limited to tertiary care centres with a special interest in mycobacterial diseases and considerable patient numbers. Furthermore, the drug is not commercially available in Belgium, and as opposed to tuberculosis, procurement for patients suffering from NTM disease was neither supported nor reimbursed until July 2025, severely restricting access. This increased the administrative and financial burden for both patients and prescribing physicians, who were already facing complex management challenges.
This study aims to document the use of clofazimine in Belgium over a ten-year period (2015–2024), focusing on its application in the management of NTM disease. By analysing indications, treatment outcomes, logistical challenges, and financial implications, the research seeks to provide guidance to prescribing physicians and inform national policymakers about the need for better drug procurement and reimbursement policies for patients with NTM disease.
Methods
This retrospective, multicentre study was performed at the University Hospitals Leuven (UZ Leuven) and Ghent University Hospital (UZ Gent) in Belgium. Ethical approval was obtained from the respective ethics committees of UZ/KU Leuven (MP 034837, S70431) and UZ Gent (S61188, S62926).
Data were collected for all patients treated with clofazimine between January 1st, 2015, and December 31st, 2024. During the study period, clofazimine was not commercially available on the Belgian market. Nevertheless, the drug was imported through international wholesalers on a named-patient basis under Belgian regulatory frameworks for unauthorized medicinal products at the patient’s expense. This was coordinated through hospital pharmacies and required both a patient-specific prescription and a physician declaration stating that no adequate authorized therapeutic alternative was available in Belgium. We identified patients through pharmacy’s dispensing records of UZ Leuven and UZ Gent, including all patients who were prescribed clofazimine in this period. Patients who did not recieve clofazimine, received clofazimine for tuberculosis and alternative non-NTM indications were excluded from analysis. For UZ Gent, clofazimine-containing regimens for NTM-extrapulmonary disease were also excluded from detailed data collection due to regulatory and ethical considerations.
A standardized data collection form was used for extraction of data from the medical records. Following data variables were collected: age, sex, pulmonary and cardiovascular comorbidities, history of organ transplant, inborn errors of immunity, chronic kidney disease, neoplastic disease (active or treated), and diabetes. Radiological features at diagnosis were categorized as cavitary, fibrocavitary, nodular bronchiectatic, mixed pulmonary, or extrapulmonary disease. Indications for clofazimine use were defined as standard therapy for MAB-PD, advanced disease, refractory disease (persistent sputum culture positivity after 6 months of guideline-based therapy), drug resistance, drug-related adverse events, or other [7]. Advanced disease was defined as cavitary, fibrocavitary, or severe bronchiectatic disease, with severe bronchiectatic disease defined as involvement of three or more pulmonary lobes on chest CT imaging. Furthermore, data regarding NTM species, clofazimine dose, accompanying drugs at the start of the clofazimine-containing regimen, duration of treatment regimen as well as duration of clofazimine intake were collected. When available, microbiological treatment outcomes were assessed. Sputum culture conversion was defined as two consecutive negative mycobacterial cultures obtained at least four weeks apart after treatment initiation. Clinical improvement and radiological stabilization or improvement were assessed based on documentation in the medical records at the end of therapy (or the last available follow-up if the former was not recorded). Adverse events were categorized into gastro-intestinal (nausea, vomiting or diarrhoea), skin toxicity (any), liver toxicity (any grade), prolonged corrected QT (QTc) interval (> 450ms for men and > 460ms for women) and other adverse events [7]. To address logistical and financial challenges, we systematically collected data on reimbursement requests submitted to the Bijzonder Solidariteitsfonds/Fonds Spécial de Solidarite/FSS (RIZIV/INAMI), as well as other available reimbursement options such as the Belgian Cystic Fibrosis Association (BCFA). For each request, information on the submission and approval dates was recorded [10].
Continuous variables are summarized as median and interquartile range (IQR) because of their non-normal distribution, while categorical variables are reported as absolute numbers and percentages. Given the descriptive nature of the study, no formal hypothesis testing was performed. Analyses were conducted using available data, and denominators are reported where relevant.
Results
Figure 1 details the recruitment process. Overall, 121 clofazimine-based regimens were prescribed over a 10-year period.
Fig. 1.
Patient enrolment flowchart
Median age at start of the regimen was 62 years (IQR 42–70), 52.1% were female; 56.4% had bronchiectasis, 28.7% COPD, and 12.8% cystic fibrosis (CF). Other baseline characteristics are presented in Table 1.
Table 1.
Demographics and comorbidities of NTM-PD and NTM-EPD patients receiving clofazimine
| Baseline characteristics | UZ Leuven (n = 61) |
UZ Gent (n = 33) |
Total (n = 94)a |
|---|---|---|---|
| Median age at start of therapy, yrs (IQR) | 69 (65–73) | 41 (24–54) | 62 (42–70) |
| Female sex, n (%) | 33 (54.1%) | 16 (48.5%) | 49 (52.1%) |
| Underlying lung disease | 50 (82.0%) | 29 (87.9%) | 79 (84%) |
| Bronchiectasis | 38 (62.3%) | 15 (45.5%) | 53 (56.4%) |
| COPD | 14 (22.9%) | 13 (39.4%) | 27 (28.7%) |
| Chronic aspergillosis | 9 (14.8%) | 2 (6.1%) | 11 (11.7%) |
| Asthma | 7 (11.5%) | 3 (9.1%) | 10 (10.6%) |
| Cystic fibrosis | 7 (11.5%) | 5 (15.2%) | 12 (12.8%) |
| Other* | 6 (9.8%) | 8 (24.2%) | 14 (14.9%) |
| Cardiovascular disease** | 29 (47.5%) | 7 (21.2%) | 36 (38.2%) |
| Organ transplant | |||
| Lung | 2 (3.2%) | - | 2 (2.1%) |
| Haematological | 1 (1.6%) | - | 1 (1.1%) |
| Kidney | 1 (1.6%) | - | 1 (1.1%) |
| Liver | - | 1 (3.0%) | 1 (1.1%) |
| Inborn errors of immunity | 6 (9.8%) | 1 (3.0%) | 7 (7.1%) |
| Chronic kidney disease | 9 (14.7%) | 3 (9.1%) | 12 (12.8%) |
| Malignancy | 10 (16.4%) | 5 (15.2%) | 15 (15.9%) |
| Diabetes | 7 (11.4%) | 3 (9.1%) | 10 (10.6%) |
IQR Interquartile range
a94/102 because exclusion of extrapulmonary cases from UZ Gent. *Prior tuberculosis (n = 3), idiopathic pulmonary fibrosis (n = 2), allergic bronchopulmonary aspergillosis (n = 2), previous lobectomy, Nocardia infection, pectus excavatum, pulmonary graft versus host disease, extrinsic allergic alveolitis (n = 2), pneumothorax, pulmonary embolism **Any of the following: myocardial infarction, angina, stroke/transient ischemic attack, coronary artery bypass graft, congestive cardiac failure, pulmonary hypertension, atrial fibrillation, arterial hypertension
The most common indication for clofazimine use was NTM disease, including 61 and 41 treatment courses in UZ Leuven and UZ Gent, respectively. Clofazimine was prescribed as part of a multidrug resistant tuberculosis (MDR-TB) treatment regimen in 4 and 12 patients from UZ Leuven and UZ Gent, respectively. A steady increase in clofazimine use was noted over time (Fig. 2).
Fig. 2.
Trend in clofazimine use for NTM-disease over time. Abbreviations: NTM, nontuberculous mycobacteria; UZL, University Hospitals Leuven; UZG, Ghent University Hospital
For NTM-disease, the main indication to use clofazimine was NTM-PD (n = 82; 80.4%), while the remaining cases involved NTM-extrapulmonary disease (NTM-EPD) (n = 20; 19.6%). In both NTM-PD and NTM-EPD, the most frequently identified species were MAC (n = 50; 61.0% and n = 7; 35.0% respectively) and MAB (n = 23; 28.0% and n = 6; 30.0% respectively). A detailed overview, including subspecies, is presented in Table 2.
Table 2.
NTM disease manifestations and species distribution in 102 clofazimine-based treatment episodes
| Disease specifications | UZ Leuven (n = 61) | UZ Gent (n = 41) | Total (n = 102) |
|---|---|---|---|
| Underlying disease | |||
| NTM-PD | 49 (80.3%) | 33 (80.5%) | 82 (80.4%) |
| Nodular bronchiectatic | 21 (42.9%) | 11 (33.3%) | 32 (39.0%) |
| Fibrocavitary | 6 (12.2%) | 15 (45.4%) | 21 (25.6%) |
| Cavitary | 11 (22.4%) | 4 (12.1%) | 15 (18.3%) |
| Mixed | 8 (16.3%) | 2 (6.0%) | 10 (12.2%) |
| Other* | 3 (6.1%) | 1 (3.0%) | 4 (4.9%) |
| NTM-EPD | 12 (19.7%) | 8 (19.5%) | 20 (19.6%) |
| Species in NTM-PD | |||
| M. avium complex | 29 (59.2%) | 21 (63.6%) | 50 (61.0%) |
| M. avium | 20 (40.8%) | 12 (36.4%) | 32 (39.0%) |
| M. intracellulare | 6 (12.2%) | 7 (21.2%) | 13 (15.9%) |
| M. chimaera | 3 (6.1%) | 2 (6.1%) | 5 (6.1%) |
| M. abscessus complex | 16 (32.7%) | 7 (21.2%) | 23 (28.0%) |
| M. abscessus | 13 (26.5%) | 3 (9.1%) | 16 (19.5%) |
| M. massiliense | 3 (6.1%) | 3 (9.1%) | 6 (7.3%) |
| M. boletii | - | 1 (3.0%) | 1 (1.2%) |
| M. xenopi | 2 (4.1%) | 1 (3.0%) | 3 (3.7%) |
| M. malmoense | 1 (2.0%) | 3 (9.1%) | 4 (4.9%) |
| M. kansasii | 1 (2.0%) | - | 1 (1.2%) |
| M. szulgai | - | 1 (6.1%) | 1 (1.2%) |
| Species in NTM-EPD | |||
| M. avium complex | 5 (41.7%) | 2 (25.0%) | 7 (35.0%) |
| M. avium | 4 (33.3%) | 1 (12.5%) | 5 (25.0%) |
| M. intracellulare | 1 (8.3%) | - | 1 (5.0%) |
| M. chimaera | - | 1 (12.5%) | 1 (5.0%) |
| M. abscessus complex | 5 (41.6%) | 1 (12.5%) | 6 (30.0%) |
| M. abscessus | 2 (16.7%) | 1 (12.5%) | 3 (15.0%) |
| M. massiliense | 2 (16.7%) | - | 2 (10.0%) |
| M. boletii | 1 (8.3%) | - | 1 (5.0%) |
| M. chelonae | 2 (16.6%) | 2 (25.0%) | 4 (20.0%) |
| M. fortuitum | - | 2 (25.0%) | 2 (10%) |
| M. genavense | - | 1 (12.5%) | 1 (5.0%) |
NTM-PD nontuberculous mycobacterial pulmonary disease, NTM-EPD nontuberculous mycobacterial extrapulmonary disease, UZ Leuven University Hospitals Leuven, UZ Gent Ghent University Hospital
*Includes tree-in-bud pattern (n = 3) and consolidation
Clofazimine was initiated as part of a first-line regimen in 58.5% of NTM-PD cases (n = 48) and in 58.3% of NTM-EPD cases (n = 7/12, only cases from UZ Leuven taken into account). Overall, the main indication for clofazimine use in NTM-PD was MAB-PD (n = 23; 28.0%), followed by advanced and refractory MAC-PD (n = 14; 17.0% and n = 10; 12.2% respectively), azithromycin-resistant MAC-PD (n = 6, 7.3%) or intolerance to another key drug (n = 23, 28.0%), specifically ethambutol and rifampicin (n = 7; 8.5% and n = 16; 19.5% respectively) (Table 3). For NTM-EPD, the main indications were advanced and refractory disease (n = 5; 41.7% and n = 4; 33.3% respectively). Other indications are presented in Tables 3 and 4 for NTM-PD and NTM-EPD respectively.
Table 3.
Indications, duration and reasons for stopping clofazimine in NTM-PD
| Clofazimine in NTM-PD | UZ Leuven (n = 49) |
UZ Gent (n = 33) |
Total (n = 82) |
|---|---|---|---|
| Indication for clofazimine | |||
| Standard therapy (MAB-PD) | 16 (32.7%) | 7 (21.2%) | 23 (28.0%) |
| Advanced disease | 3 (6.1%) | 14 (42.4%) | 17 (20.7%) |
| Advanced MAC-PD | 3 (6.1%) | 11 (33.3%) | 14 (17.0%) |
| Advanced non-MAC-PD | - | 3 (9.0%) | 3 (3.7%) |
| Refractory disease | 10 (20.4%) | 1 (3.0%) | 11 (13.4%) |
| Refractory MAC-PD | 9 (18.4%) | 1 (3.0%) | 10 (12.2%) |
| Refractory non-MAC-PD | 1 (2.0%) | - | 1 (1.2%) |
| Intolerance to a key drug | 14 (28.6%) | 8 (24.2%) | 22 (26.8%) |
| Intolerance to rifampicin | 9 (18.4%) | 6 (18.2%) | 15 (18.3%) |
| Intolerance to ethambutol | 5 (10.2%) | 2 (6.1%) | 7 (8.5%) |
| Macrolide resistant MAC-PD | 4 (8.2%) | 2 (6.0%) | 6 (7.3%) |
| Other* | 2 (4.1%) | 1 (3.0%) | 3 (3.7%) |
| Median duration of clofazimine (days, IQR) | 302 (102–499) | 402 (183–536) | 374 (130–528) |
| Ongoing clofazimine-containing regimens at data censoring | 7 (14.3%) | 6 (18.2%) | 13 (15.9%) |
| Reasons for premature discontinuation of clofazimine (n = 69, ongoing treatments excluded) | |||
| Adverse events | 11 (40.7%) | 5 (18.5%) | 16 (23.2%) |
| Stop clofazimine only | 2 (4.1%) | 3 (11.1%) | 5 (7.2%) |
| Stop entire regimen | 9 (33.3%) | 2 (7.4) | 11 (15.9%) |
| Death | 6 (22.2%) | 1 (3.7%) | 7 (16.3%) |
| Financial | - | 2 (7.4%) | 2 (2.9%) |
| Other (stop entire regimen)** | 10 (37.0%) | 6 (22.2%) | 18 (26.1%) |
Cfz clofazimine, NTM-PD nontuberculous mycobacterial pulmonary disease, UZ Leuven University Hospitals Leuven UZ Gent Ghent University Hospital, MAB-PD Mycobacterium abscessus complex pulmonary disease, MAC-PD Mycobacterium avium complex pulmonary disease IQR interquartile range
*Includes expected interactions with rifampicin, rifampicin stock rupture and fear for adverse events of ethambutol. **Includes general deterioration (n = 5), drug holiday (n = 4), macrolide susceptibility (n = 2), interactions with azoles/Cystic Fibrosis Transmembrane conductance Regulator modulating therapy (n = 2), resistance to another key drug element (n = 1) and insufficient companion drugs (n = 1), missing data (n = 3)
Table 4.
Indications, duration and reasons for stopping clofazimine in NTM-EPD at UZ Leuven
| Clofazimine in NTM-EPD | Total (n = 12) |
|---|---|
| Indication for clofazimine | |
| Advanced disease | 5 (41.7%) |
| Refractory disease | 4 (33.3%) |
| Adverse events | 2 (16.7%) |
| Resistance | 1 (8.3%) |
| Median duration of clofazimine (days, IQR) | 98 (23–256) |
| Ongoing clofazimine-containing regimens at data censoring | 2 (16.7%) |
| Reasons for premature discontinuation of clofazimine (n = 10, ongoing treatments excluded) | |
| Adverse events | 3 (30.0%) |
| Death | 3 (30.0%) |
| Other* | 1 (10.0%) |
NTM-EPD nontuberculous mycobacterial extra pulmonary disease, UZ Leuven University Hospitals Leuven, IQR interquartile range
*De-escalation to maintenance regimen without clofazimine
Figure 3 summarizes the accompanying antibiotics in the initial clofazimine-containing regimen. The most frequent clofazimine dosing regimen in NTM-PD was 100 mg daily (n = 75; 91.2%), followed by 50 mg daily (n = 4; 4.9%) and 200 mg daily (n = 3; 3.7%). Because only a very limited number of patients received higher doses clofazimine, subgroup analysis of adverse events according to dose was not feasible.
Fig. 3.
Rainbow plot showing the use of antimicrobial agents. Antimicrobial agents assessed across individual treatment regimens. Columns represent individual treatments, and rows represent specific antimicrobial agents. Orange cells indicate that the drug was prescribed, while light green cells indicate no recorded use. The antimicrobial agents are hierarchically clustered according to similarity in prescribing patterns, as shown by the left dendrogram. This clustering reflects observed real-world treatment patterns, including agents that tended to be co-prescribed, used within the same patient, or introduced following regimen modification. The figure includes all antimicrobial agents assessed in the treatment data to illustrate their recorded use or absence of use in this cohort. The annotation bars below the heatmap indicate, from top to bottom, treating hospital (UZL vs. UZG), clofazimine dose (50 mg, 100 mg, or 200 mg), and clinical indication (NTM-PD vs. NTM-EPD). Abbreviations: Cfz, clofazimine; NTM, nontuberculous mycobacteria; NTM-PD, NTM pulmonary disease; NTM-EPD, extrapulmonary nontuberculous mycobacterial disease; UZL, University Hospitals Leuven; UZG, Ghent University Hospital
The median duration of clofazimine therapy was 374 days (IQR 130–528 days) for NTM-PD and 98 days (IQR 23–256) for NTM-EPD. At data censoring, 15.9% (n = 13) of NTM-PD and 16.7% (n = 2) of NTM-EPD clofazimine-containing regimens remained ongoing. Excluding ongoing regimens, treatment completion occurred in 37.7% of NTM-PD cases (26/69) and 30.0% of NTM-EPD cases (3/10). The main reason for premature discontinuation of the entire NTM-PD treatment regimen was occurrence of adverse events (23.2%; 16/69); clofazimine only was discontinued in 5 (7.2%) cases. Other reasons are listed in Tables 3 and 4.
Adverse events of interest were gastro-intestinal complaints (mainly nausea, vomiting, diarrhoea), skin toxicity (ichthyosis and hyperpigmentation) and prolonged QTc (regardless of clinical relevance), which were reported in 52.1% (n = 49), 38.3% (n = 36) and 4.2% (n = 4), respectively.
Overall, culture conversion was obtained in 69.5% of patients with MAB (all in initial regimen, including 6 M. massiliense) and 54% of MAC cases. Among MAC-PD patients, culture conversion was higher when clofazimine was used as part of the initial treatment regimen compared with refractory disease (59.4% vs. 38.4%) (Table 5).
Table 5.
NTM-PD treatment outcomes at last follow-up or data censoring
| NTM-PD treatment outcomes | Overall n/N (%) | First line/substitution therapy n/N (%) | Refractory disease n/N (%) |
|---|---|---|---|
| Sputum culture conversion | 49/82 (59.7%) | ||
| M. abscessus complex (n = 23) | 16/23 (69.5%) | 16/23 (69.5%) | - |
| M. avium complex (n = 50) | 27/50 (54%) | 22/37 (59.4%) | 5/13 (38.4%) |
| Other species | 6/8 (75.0%) | ||
| M. malmoense | 3/4 (75.0%) | 3/4 (75.0%) | - |
| M. xenopi | 1/2 (50.0%)* | 1/2 (50.0%) | NA* |
| M. szulgai | 1/1 (100.0%) | 1/1 (100%) | - |
| M. kansasii | 1/1 (100.0%) | 1/1 (100%) | - |
| Clinical improvement | 49/82 (59.7%) | ||
| Radiological stabilisation/improvement | 54/82 (65.9%) |
Sputum culture conversion was defined as two consecutive negative mycobacterial cultures obtained at least four weeks apart after treatment initiation. First-line/substitution therapy refers to clofazimine use as part of initial treatment or as replacement of another key drug because of intolerance. Refractory disease was defined as persistent culture positivity after at least six months of guideline-based therapy.
NTM-PD nontuberculous mycobacterial pulmonary disease, NA not applicable
*One patient with refractory M. xenopi pulmonary disease had unavailable microbiological follow-up data and was therefore excluded from sputum culture conversion analysis
Considering logistical and financial implications, financial reimbursement requests for clofazimine were submitted for 68.2% of all NTM-PD treatments (38/49 (77.6%) in UZ Leuven, 18/33 (54.5%) in UZ Gent), mostly at FSS/BSF and the BCFA. The majority was granted partial approval albeit after a delay of 6 months or more.
Discussion
We described our 10-year experience of clofazimine use focusing on NTM disease in the two largest NTM referral centres in Belgium. Despite its restricted access and high financial burden, clofazimine prescriptions for NTM disease have shown a clear upward trend over the past decade (Fig. 2), reflecting the uptake of international guideline recommendations [11–13].
As anticipated, most patients were treated for pulmonary infections, the predominant clinical manifestation of NTM disease [7]. Clofazimine was prescribed as part of a first-line regimen in all pulmonary and in nearly all disseminated MAB treatments (100% and 80% respectively), as well as in azithromycin-resistant MAC treatments. This aligns with the latest clinical practice guidelines including the 2020 ATS/ERS/ESCMID/IDSA recommendations and earlier consensus statements from the US CF Foundation and the European CF Society, in which clofazimine is considered a first-line oral drug for MAB-PD and for macrolide-resistant MAC disease [7, 14]. These guidelines also recommend clofazimine as an alternative in case of intolerance to rifampicin or ethambutol, which was the case in 17.5% and 8.5% respectively in our cohort. Moreover, a recent study by Sallilas et al. demonstrated that, compared with rifampicin-based therapy, clofazimine-containing regimens had superior antimycobacterial activity and prevented the development of macrolide resistance in an intracellular hollow-fibre infection model [15]. This supports the growing evidence of upfront use of clofazimine as a substitute for rifampicin, which lacks direct antimycobacterial activity and is known for its drug-drug interactions. Clinical trial data however remain limited: Zweijpfenning et al. performed a single-centre, open-label trial, which randomised 40 adult MAC-PD patients (19 vs. 21) to either clofazimine or rifampicin to an ethambutol-macrolide backbone and showed similar outcome in both arms [16]. Another RCT is ongoing (NCT02968212).
Although efficacy was not the primary focus of this study, microbiological outcome data were available for a substantial proportion of patients. Overall, sputum culture conversion was achieved in 69.5% of patients with MAB-PD and 59.4% of patients with non-refractory MAC-PD. Nevertheless, the observed culture conversion rates are broadly in line with previously reported outcomes including 50% at 12 months in the study by Martiniano et al. (99 patients with pulmonary NTM disease) and 51.6% in the prospective study by Watanabe et al. (64 patients with MAC-PD and MAB-PD) [17, 18].
The most frequent dosing regimen was clofazimine 100 mg daily, in accordance with recommendations in the joint ATS/ERS/ESCMID/IDSA clinical practice guideline for NTM pulmonary disease [7, 19]. It should be emphasized that clofazimine requires several months to achieve steady-state plasma concentration. A recent pilot study from Stemkens et al. confirmed the safety and tolerability of higher clofazimine loading doses, which shortened the time to target plasma concentrations [20]. Further prospective studies are warranted to determine whether the use of a loading dose truly leads to improved clinical outcome.
Clofazimine was generally well tolerated. One in five experienced adverse events leading to early treatment discontinuation: 15% prematurely discontinued the entire regimen, 7.2% stopped clofazimine only. This compares favourably to the 14% treatment discontinuation rate attributed to clofazimine-related adverse events in a recent Dutch-Italian retrospective cohort (22). A recent systematic review and meta-analysis of 36 prospective studies reported discontinuation rates of approximately 15% during multidrug therapy [21]. Treatment interruptions and regimen modifications are common in NTM-PD management and are often influenced by host factors, comorbidities, treatment duration, multidrug regimens and disease severity rather than by mycobacterial species. In our study, most reported adverse events were of gastro-intestinal nature, including nausea, vomiting and/or diarrhoea (52.1%), although inadequate follow-up time of some patients may have biased our results. Similar findings have been reported in previous studies and are very often associated with azithromycin, a key drug in these multidrug regimens [16, 18, 22]. A substantial proportion of the patients in our cohort had advanced or refractory disease, reflecting the tertiary referral setting of both participating centres, where clofazimine was often considered in clinically complex cases.
Skin-related toxicity, primarily hyperpigmentation, occurred in 38.3% of patients, though prior reports have documented rates as high as 75–100% [17, 18, 22, 23]. However, more recent NTM cohorts have reported lower frequencies ranging from 26% to 60% [24, 25]. Several factors may explain the lower observed frequency, including the absence of a standardized assessment tool, variability in documentation practices, differences in cumulative exposure and treatment duration, incomplete follow-up in some patients, and potential differences in skin phototypes although the majority of patients were Western European Caucasians. Clofazimine-induced skin pigmentation is generally reversible but may persist for several months, with the degree and duration of pigmentation correlating with cumulative dose and serum concentration. Notably sun-exposed areas are typically more affected [22, 26]. We therefore endorse the advice to counsel patients regarding its potential impact [27].
Our study found that 4 patients had a prolonged QTc interval, though QTc was not systematically reported in the medical files. This low observed rate of prolonged QTc is consistent with limited published data, which shows that clofazimine is associated with a concentration-dependent increase in QTc interval, although clinically significant QTc prolongation (QTc ≥ 500 ms) is uncommon in adult cohorts treated for NTM or tuberculosis [16, 17, 20, 22, 28]. Several studies highlight that the risk of prolonged QTc interval is substantial when clofazimine is combined with other QT-prolonging agents such as macrolides, bedaquiline or fluoroquinolones, and underscore the need for regular ECG monitoring during therapy as recommended by the joint ATS/ERS/ESCMID/IDSA clinical practice guideline [7, 29, 30].
To overcome adverse events and improve efficacy, inhaled clofazimine for NTM-PD has been studied in preclinical studies, in vitro models, and in early-phase human pharmacokinetic and safety studies. Although animal models and healthy-volunteer studies demonstrated that inhaled clofazimine achieved high and sustained lung tissue concentrations with minimal systemic exposure, the ICoN-1 trial (NCT06418711), a phase 3 trial assessing the efficacy and safety of clofazimine inhalation suspension added to guideline-based therapy for NTM-PD, was discontinued because of futility following interim analysis [31, 32].
Despite the orphan drug designation for clofazimine for the treatment of NTM-PD by the European commission in August 2019, important administrative and financial barriers still influenced treatment decisions in Belgium [33]. Notably, two patients discontinued therapy prematurely due to financial constraints; similar (financial/logistic) barriers may have influenced clinicians not to consider clofazimine for eligible patients.
Reimbursement requests – the majority to the national health insurance authority – were filed in 68.2% of all NTM-PD treatments. Sustained efforts to obtain reimbursement ultimately resulted in approval of national health insurance coverage of clofazimine for NTM disease management in Belgium as of July 2025. It is also important to note that clofazimine remains commercially unavailable in Belgium, a challenge shared by more than half of European countries, making importation from neighbouring states necessary [34].
Finally, the retrospective nature of this study has several limitations. First, although this study was conducted at the two largest NTM-referral centres, it may not fully represent the national landscape of clofazimine use in Belgium. Second, differences in data collection variables between centres may have introduced heterogeneity in the available data, and reimbursement data may be incomplete. Third, although microbiological outcome data were available for the majority of patients, the heterogeneity of the study population, including differences in NTM species, disease severity, treatment indications and accompanying antimicrobial regimens, together with the retrospective design and absence of a comparator group, limits assessment of the specific contribution of clofazimine to treatment outcomes.
Conclusions
This study underscores the clinical indications and overall acceptable tolerability of clofazimine in NTM disease management, in line with international guidelines, despite the logistical and administrative hurdles procuring the drug in Belgium. Thanks to the recent coverage of clofazimine by the national health insurance, clofazimine-containing regimens are likely to become more widely used in the coming years, potentially improving patient outcomes.
Supplementary Information
Acknowledgements
We would like to express our gratitude to Maud Kovac, Pharmacy student, for her valuable assistance with data collection at UZ Leuven. For UZ Ghent, we extend our thanks to study coordinator Stefanie Vermeersch for her support during the data collection process and for her help in arranging the ethics committee approval.
Abbreviations
- ATS
American Thoracic Society
- Cfz
Clofazimine
- ERS
European Respiratory Society
- ESCMID
European Society of Clinical Microbiology and Infectious Diseases
- IDSA
Infectious Diseases Society of America
- COPD
Chronic obstructive pulmonary disease
- CF
Cystic Fibrosis
- NTM
Nontuberculous mycobacteria
- NTM-PD
Nontuberculous mycobacterial pulmonary disease
- NTM-EPD
Nontuberculous mycobacterial extrapulmonary disease
- MDR-TB
Multidrug resistant tuberculosis
- MAB
M. abscessus complex
- MAB-PD
M. abscessus complex pulmonary disease
- MAC
M. avium complex
- MAC-PD
M. avium complex pulmonary disease
- RIZIV/INAMI
Rijksinstituut voor Ziekte- en Invaliditeitsverzekering / Institut National d’Assurance Maladie-Invalidité
- BCFA
Belgian Cystic Fibrosis Association
- BSF/FSS
Bijzonder Solidariteitsfonds / Fonds Spécial de Solidarité
- UZ Leuven
University Hospitals Leuven
- UZ Gent
Ghent University Hospital
Authors' contributions
AP, SM, EVB, NL conceived the study; AP, SM collected the data and wrote the first draft. AP, SM, NJ, YVW, NL conducted data analysis and contributed to interpretation of results. YVW, EVB, NL supervised the project and YVW, EVB, NL revised the manuscript. All authors reviewed and approved the final manuscript.
Funding
None.
Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
Ethical approval was obtained from the respective ethics committees of UZ/KU Leuven (MP 034837, S70431) and UZ Gent (S61188, S62926).
Consent for publication
Not applicable.
Competing interests
E.VB.’s and N.L.’s institution received financial support from Insmed for the conduct of clinical trials, consultancy, advisory boards and lectures in the field of NTM-PD. All other authors declare no conflicts of interest.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Astrid Piot and Sophie Missault contributed equally to this work.
Contributor Information
Astrid Piot, Email: astrid.piot@uzleuven.be.
Sophie Missault, Email: sophie.missault@ugent.be.
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Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.