Heart failure & cardiomyopathies
Incidence, Timing and Clinical Significance of Immune-Mediated Myocardial Injury and Myocarditis After Gene Replacement Therapy: A Systematic Review and Meta-Analysis
Authors' conclusion
Immune-mediated myocarditis/myocardial injury after systemic AAV gene therapy occurred in <10 per 100 patient-years (peaking at weeks 1-3) and was usually clinically mild, with a minority showing transient dysfunction. All events followed intravenous doses >1×10 1 3 vector genomes per kilogram body weight, clustered in neuromuscular programs, and were associated with certain recombinant capsids/serotypes. These data support intensive early cardiac monitoring, cautious dose selection, and delivery strategies to minimize systemic exposure.
Study context
- Population
- Patients treated with adeno-associated virus (AAV)-replacement therapyhuman patients in 80 studies
- Participants
- 1,939 patients
- Outcome
- Myocarditis incidence rate per 100 patient-years
Methodological detailsrandom-effects models, restricted maximum likelihood estimation, Hartung, Knapp, Sidik, and Jonkman method, pharmacovigilance search of VigiBase and FDA Adverse Event Reporting System
- Random-effects models
- Restricted maximum likelihood estimation
- Hartung, Knapp, Sidik, and Jonkman method
- Pharmacovigilance search of VigiBase and FDA Adverse Event Reporting System
Pooled result
As reported in the abstract
- Cases of myocarditis
- Seventy-one
- Pooled incidence rate per 100 patient-years
- 8.6 (95% CI, 5.8-10.7; I 2 =63.2%)
Further pooled results
Timing of myocardial injury and myocarditis
- Myocardial injury peaked in week 1 after injection
- 90% [95% CI, 85.7%-96.2%]; I 2 =43.2%
- Myocarditis occurred mostly after week 2
- 55% [95% CI, 48.7%-65.2%]; I 2 =33.1%
- No cases after the first month
Clinical impact of myocarditis/myocardial injury
- No relevant clinical impact
- 62, 87%
- Transient left ventricular dysfunction (recovered during follow-up)
- 8 (12%)
- Only death, in the setting of cytokine-mediated capillary leak syndrome with cardiac dysfunction
Myocarditis in FDA Adverse Event Reporting System and VigiBase
- Delandistrogene moxeparvovec
- 1/16 [6%]
- Onasemnogene abeparvovec
- 14/217 [6%]
Adverse events and observation
- Adverse events reported
- 734
- Patient-years of pooled observation
- 2122
- All events followed an intravenous dose >10 13 vector genomes per kilogram body weight
Original publication
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