Leprosy Mailing List – August 3, 2026
Ref.: (LML) Long-lasting adverse impact of chemoprophylaxis & what actually works
From: Benedict Quao, Cape Coast, Ghana
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Dear colleagues,
Although the Leprosy Mailing List Blog is an open forum for sharing information among people working in the field of leprosy, and thus not set up for scientific discussions, we would like to encourage readers to critically evaluate the evidence supporting the conclusions on Single Dose Rifampicin (SDR) as Post-Exposure Prophylaxis (PEP) presented in this email from Dr. Joel Almeida. While novel hypotheses are an important part of scientific progress, they should be clearly distinguished from conclusions supported by robust experimental or epidemiological evidence. In Dr. Almeida's recent email, several statements are presented as established facts despite remaining speculative or not being supported by the cited literature.
Below are a few examples:
1. Interpretation of the PEP-Hans data
The comparison between former PEP-Hans municipalities and non-PEP municipalities cannot be interpreted as evidence that chemoprophylaxis increased the risk of multibacillary (MB) leprosy or grade 2 disability (G2D). There were 16 PEP-Hans municipalities, which were specifically selected based on their classification as priority municipalities for leprosy by Brazil’s MOH. Comparing these municipalities to an unspecified number of other non-priority areas for leprosy with much higher total annual new leprosy case numbers collectively, years later, introduces substantial selection bias. Moreover, there is no clear indication that the comparator (non-PEP) municipalities are of comparable endemicity, nor is it evident that the duration of data collection was equivalent between the intervention and comparison groups, further limiting the validity of the comparison.
In addition, the figures presented begin only one year before the implementation of PEP. This provides an inadequate baseline for assessing the impact of the intervention. A substantially longer pre-intervention period (e.g., at least 5–10 years) is necessary to establish the underlying epidemiological trends and determine whether any observed changes differ from the historical trajectory of these municipalities. In the absence of such an extended baseline period, the incidence data should, at minimum, be normalised, and municipalities with substantially divergent baseline incidence trends should be excluded from the comparison.
Furthermore, the proposed temporal relationship is biologically implausible. M. leprae is an extremely slow-growing pathogen, and leprosy usually develops only after a prolonged incubation period, typically over several years. Consequently, any intervention that genuinely altered the risk of developing MB disease would not be expected to produce an immediate increase in incident MB cases or disease prevalence within a municipality. Any claim that PEP rapidly increased MB disease would therefore require exceptionally strong epidemiological evidence, which is not provided here. It is also worth noting that between 2022 and 2024, contact tracing intensified substantially in PEP municipalities than in non-PEP municipalities, which could independently increase case detection and thereby inflate the apparent proportion of MB cases.
Demonstrating a detrimental effect of PEP would require analyses accounting for baseline incidence, surveillance intensity, demographic differences, and other potential confounders, including the COVID-19 impact. An ecological comparison alone cannot establish causality.
2. Interpretation of the STING/OASL study
The study by de Toledo-Pinto et al. (ref 3) demonstrated that viable intracellular M. leprae can activate the cGAS-STING-OASL pathway, thereby promoting bacterial survival by modulating autophagy. In fact, their paper explicitly stated that the mechanisms underlying the direction of response following infection are not clearly understood, with the mycobacterial burden presented during infection being the most likely determinant – i.e. a low mycobacterial infective burden is more likely to result in autophagy and control of the infection, and vice versa. Furthermore, it did not investigate the effects of rifampicin-killed bacilli or demonstrate that bacterial debris generated by chemoprophylaxis produces prolonged suppression of macrophage function. Extending these findings to conclude that chemoprophylaxis "disarms" macrophages is therefore unsupported.
3. Persistence of bacterial debris
The statement that bacterial debris persists beyond the duration of chemoprophylaxis and continues to suppress macrophage function is presented without supporting evidence. This would require experimental demonstration of prolonged persistence of bacillary components together with sustained impairment of macrophage antimicrobial responses. To date, such evidence has not been demonstrated.
4. Emergence of "high-virulence" bacilli
The cited work on mycobacterial pole elongation (ref 4) describes normal bacterial growth dynamics. It does not demonstrate that antimicrobial exposure generates phenotypically more virulent M. leprae, nor that surviving bacilli express increased virulence factors following chemoprophylaxis. No experimental, transcriptomic, or genomic evidence currently supports this conclusion.
5. Linking these mechanisms to increased MB disease and disability
The proposed sequence of events (chemoprophylaxis kills bacilli, bacterial debris suppresses macrophages, surviving bacilli become more virulent, leading to increased MB disease and G2D) is entirely hypothetical. None of the intermediate steps are supported by the cited references. While this may represent an interesting biological hypothesis worthy of investigation, it should not be presented as an established mechanism. Public health recommendations should be based on robust experimental and epidemiological evidence, not on speculative mechanistic models that have yet to be validated.
6. Expected effects of chemoprophylaxis
Clinical trials have consistently shown that chemoprophylaxis partially reduces the risk of developing leprosy. Limited efficacy should not be interpreted as evidence of harm.
7. Asymptomatic "high shedders" as the main reservoir of transmission
Dr. Almeida further attributes the marked decline in new MB cases in São Luís, Maranhão to the identification and treatment of these presumed "high shedders." However, this conclusion is not supported by the evidence presented.
(A) A reduction in case numbers may result from multiple factors, including intensified case detection, earlier diagnosis, prompt treatment of clinically affected individuals, improved contact tracing, changes in surveillance practices, and broader public health interventions. Without an appropriate epidemiological analysis accounting for these potential confounders, it is not possible to attribute the observed decline specifically to the treatment of asymptomatic individuals.
(B) More fundamentally, the existence of a population of asymptomatic individuals who consistently shed large quantities of viable M. leprae and represent a major driver of transmission has not been demonstrated.
Molecular studies have detected M. leprae DNA (and in some cases RNA1) in nasal swabs from asymptomatic individuals2, but there is currently no convincing evidence that these individuals represent clinically silent lepromatous disease, that they consistently shed viable bacilli, or that they account for a substantial proportion of transmission. Their prevalence, duration of carriage, infectiousness, and public health significance remain unknown and is not reported in any publication cited by Dr. Almeida.
In this context, the email also states that Maranhão has implemented semi-quantitative mLAMP to identify individuals shedding M. leprae. However, no supporting reference or validation study is provided.
(C) More importantly, if the hypothesis is based on the detection of M. leprae DNA alone, the conclusion is not justified. Detection of bacterial DNA in nasal secretions demonstrates only that bacterial genetic material is present; it does not establish that intact, viable bacilli are being shed. DNA may persist after bacterial death or originate from non-viable organisms. In contrast, detection of bacterial RNA provides substantially stronger evidence for viable, metabolically active bacilli and is currently the most appropriate molecular approach for assessing bacterial viability. Therefore, conclusions regarding infectiousness or transmission cannot be based solely on DNA detection.
In summary, the interpretation presented does not consistently follow the scientific process by which observations are critically analysed before causal conclusions are drawn. Scientific reasoning requires that hypotheses be tested against the available evidence, that alternative explanations and potential confounding factors be considered, and that conclusions remain proportional to the strength of the supporting data. In several instances, hypotheses are presented as established mechanisms and causal relationships without sufficient experimental or epidemiological evidence to support those interpretations.
On behalf of the ILEP Technical Commission,
Benedict Quao
References
1. Beissner M, Woestemeier A, Saar M, Badziklou K, Maman I, Amedifou C, et al. Development of a combined RLEP/16S rRNA (RT) qPCR assay for the detection of viable M. leprae from nasal swab samples. BMC Infect Dis 2019;19:753. https://doi.org/10.1186/s12879-019-4349-9.
2. Gama RS, Gomides TAR, Gama CFM, Moreira SJM, de Neves Manta FS, de Oliveira LBP, et al. High frequency of M. leprae DNA detection in asymptomatic household contacts. BMC Infect Dis 2018;18:153. https://doi.org/10.1186/s12879-018-3056-2.
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LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << edit...@gmail.com
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