Leprosy: a disease still beyond control

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, characterized by marked clinical, immunological, and evolutionary heterogeneity. Despite a substantial reduction in global prevalence following the introduction of multidrug therapy (MDT), annual incidence rates remain stable, indicating ongoing transmission. Current treatments have significantly reduced disease burden but have not achieved eradication. They are also increasingly challenged by the emergence of drug resistance, particularly to rifampicin. Preventive strategies rely mainly on chemoprophylaxis and BCG vaccination, both of which show partial and inconsistent effectiveness. 

Major challenges include an incomplete understanding of pathophysiology, the central yet complex role of the host immune response, and the critical influence of genetic factors on susceptibility, clinical presentation, and leprosy reactions. In this context, this study was undertaken to synthesize recent evidence on treatments, prevention strategies, immune mechanisms, and genetic determinants of leprosy, with the aim of identifying levers to improve disease control.

This study integrates epidemiological, clinical, immunological, and genetic data derived from observational studies, clinical trials, experimental research, and genetic association studies. The effectiveness and limitations of multidrug therapy were assessed, along with preventive strategies among contacts. Immune mechanisms and genetic susceptibility factors underlying the clinical heterogeneity of the disease were also examined, in order to provide an integrated view of the biological and therapeutic determinants of leprosy.

Current evidence shows that chemoprophylactic strategies, particularly single-dose rifampicin and rifapentine, significantly reduce the risk of disease among contacts, but do not confer durable protection. From an immunological perspective, the review highlights the key role of immune response polarization, contrasting protective Th1/Th17 responses with Th2/Treg responses associated with multibacillary forms. M. leprae targets several host cell types, including macrophages, Schwann cells, keratinocytes, and dendritic cells, subverting their metabolic and immune functions. Finally, genetic analyses identify more than 30 susceptibility genes involved in bacterial recognition, autophagy, cytokine signaling, and antigen presentation, confirming that leprosy is strongly modulated by the host genetic background.

Leprosy remains a complex infectious disease at the crossroads of microbiology, immunology, and genetics. The main challenges identified include persistent transmission, emerging drug resistance, the lack of a disease-specific vaccine, and limitations in early diagnosis. The objective of this review was to provide an integrated synthesis of therapeutic, preventive, immunological, and genetic data to improve the overall understanding of the disease. The findings clearly demonstrate that sustainable leprosy control cannot rely on antibiotics alone, but requires a combined strategy integrating targeted prevention, immune response modulation, and identification of high-risk genetic profiles.

This study nevertheless has limitations—including the absence of a complete experimental model and the heterogeneity of studied populations—which justify the need for further research. Future efforts will focus on the development of more effective vaccines, the identification of immunogenetic biomarkers for early detection, and the exploration of new therapeutic targets aimed at pathways exploited by M. leprae.