Leprosy Mailing List – August 7, 2026
Ref.: (LML) Long-lasting adverse impact of chemoprophylaxis & what actually works
From: Joel Almeida, Mumbai, India
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Dear Pieter and colleagues,
Respectful thanks to the correspondent (Dr. Benedict Quao) for his interest in the original letter (LML 9 and 11 July 2026).
Low‑income individuals are disproportionately represented among new HD (leprosy) cases and their families. Many have minimal schooling, and rely on manual labour to escape destitution and hunger. Safeguarding their eyes, hands and feet is therefore paramount. This is why so many esteemed colleagues are working to match the rapid declines in MB HD (multibacillary leprosy) documented in Weifang (China), Malta, Jordan, Chile, Vietnam, Thailand, Karonga, Ecuador and elsewhere—using steadily improving diagnosis and full free antimicrobial treatment together with regular check-ups, without chemoprophylaxis. It is also why, in endemic areas, nasal swabs from ALL asymptomatic individuals are needed, to identify cryptic LL high‑shedders and rapidly end transmission.
The correspondent doubts that asymptomatic individuals exist who shed large quantities of viable M. leprae. Yet Davey and Rees (1974, Lepr Rev 45(2):121–34) provided clear evidence:
“Highly bacilliferous discharges were encountered in early lepromatous leprosy, indicating nasal involvement far more severe than external appearances suggested… millions of bacilli are discharged daily in nasal secretions from lepromatous patients with active and, importantly, early disease. When these millions of bacilli are being discharged from the nose the patients may well be unaware that they have leprosy and clinically they have insignificant skin lesions…”
They estimated "an average output/day from the nose of an active lepromatous patient of 31 ,000,000 live organisms and an average of 19,000,000 live Myco. leprae from a single early morning specimen of nasal discharge" Without bacillary replication in the nose, it is very difficult to explain how nearly 20 million bacilli appear in one specimen of nasal discharge. These facts illustrate why nasal swabs from all asymptomatic persons in a cluster, analysed by semi‑quantitative mLAMP (DNA or RNA as desired), are critical for prompt full treatment and rapid reduction of transmission. Semi-quantitative means those who shed astronomical numbers of bacilli in nasal discharges are distinguished from transient nasal carriers of trivial numbers of bacilli.
Regarding São Luís (Maranhão), where no chemoprophylaxis was used: the original letter noted that it is “producing among the world’s most rapid declines of new MB HD: e.g. from 279 new MB in 2023 to only 200 in 2025.” It further stated that introducing nasal swabs for semi‑quantitative mLAMP could accelerate this decline and end transmission within weeks. That was the intended message. Extending the point: failure to introduce nasal swabs for ALL asymptomatics risks missing cryptic LL high shedders. That can keep open the floodgates of infection, putting at risk São Luís’ remarkable achievements.
When serious harm is demonstrated from an intervention, the burden of proof shifts to proponents of the intervention to demonstrate safety.
What does the RCT evidence show? All RCTs failed to report on incident G2D (visible deformity at diagnosis) as an outcome. However, three RCTs reported incident MB HD as an outcome. MB carries a far higher risk of nerve damage than PB (Croft et al 2000 Lancet) and is therefore a useful proxy for risk of G2D. Contrary to the correspondent’s assertion, an excess of incident MB cases in arm 2 (household‑contact PEP clusters) versus arm 1 (non‑PEP control clusters) is evident in raw RCT data. Two of the only three RCTs that included incident MB HD as an outcome—PEOPLE and MALTALEP—show this excess o incident MB. Incident MB is an outcome, not a subgroup; the denominator is the same as for all other outcomes. The third RCT (COLEP), at full protocol duration (4 years), showed no statistically valid protection against incident MB HD, and incident MB cases even increased numerically between years 1/2 and 3/4, contrasting with a concurrent 40% DECREASE in incidence in the PLACEBO arm. This contrast between rapid decline in the placebo group and concurrent INCREASE in the chemoprophylaxis arm is important, as is excess incident MB HD in household PEP arm 2 clusters vs non-PEP arm 1 clusters of the other two RCTs. Contacts who received short‑term chemoprophylaxis and then developed visible deformity before diagnosis will derive no comfort from concealment of RCT signals of harm. They are not in a position to gamble with their eyes, hands and feet.
Further evidence of harm comes from India, indicating that short‑term chemoprophylaxis is an important factor in causing visible deformity before diagnosis (Ind J Lepr 2026, 97:175-188). The article is available at: https://doi.org/10.5281/zenodo.21344996
The correspondent apparently also overlooked the most relevant part of the OASL article by de Toledo Pinto et al. (2016) who reported:
“MdTHP‑1 cells [macrophages] were lipofected with M. leprae DNA… IFNB and OASL mRNA levels were significantly increased after 72 hours of infection, compared with the unlipofected culture.”
Lipofection means that foreign DNA within liposomes (fat droplets) was delivered into the cytosol of macrophages. This was M. leprae DNA: neither killed bacilli nor live bacilli.
Given established biology:
1. One or a few antimicrobial doses damage intracellular bacilli, producing bacillary debris in macrophage cytosol.
2. Cytosolic bacillary DNA activates cGAS → cGAMP → STING → IRF3 → IFN‑β.
3. IFN‑β upregulates OASL, which suppresses autophagy and cathelicidin.
Autophagy is the primary mechanism by which macrophages clear debris and bacilli. Vitamin‑D‑induced cathelicidin is a critical antimicrobial peptide.
Cytosolic DNA sensing via cGAS is foundational immunology, grounded in the work of Zhijian “James” Chen (Lasker Award 2024, Japan Prize 2026 etc.). The default expectation is that this highly conserved and universal sequence occurs. Proponents of PEP must demonstrate how and why it is uniquely absent in the case of bacillary debris produced by one or a few antimicrobial doses. That burden of proof is nowhere near being discharged.
When bacilli replicate by elongation, their surface area increases, and their numbers increase. Given the role of the surface virulence factor PGL‑1 in non‑inflammatory nerve damage (Madigan et al., Cell 2017 http://dx.doi.org/10.1016/j.cell.2017.07.030 ), and the surface virulence factor Mce1A in cell entry (Fadlitha et al 2019 https://doi.org/10.1371/journal.pntd.0006704 ) proponents of PEP must demonstrate that actively replicating bacilli are phenotypically safer for humans than dormant bacilli: less invasive and less damaging to nerves. That burden is nowhere near being discharged.
The PEPHans vs non‑PEP comparison in the original letter(s) (9 and 11 July) aligns with convergent patterns across multiple datasets and biological levels. %G2D (visible deformity at diagnosis) normally indicates delayed diagnosis. Yet the displayed data show that intensified active case finding (increased proportion detected by contact tracing) was accompanied by an increase—not a decrease—in %G2D. This reversal of the usual pattern occurred only in PEPHans areas. Biological acceleration of nerve damage is expected to result in a significantly higher percentage of new cases presenting with G2D as the first detectable sign of HD in PEP areas. PEPHans began in 2016, continued till 2019, and the harms remained evident as recently as 2024.
The new case detection rate of MB HD in the PEPHans municipalities was similar to the non-PEP areas of Maranhão (around 4 to 5 per 10k population/year) until the dramatic drop attributable to COVID disruptions. The physical distancing of COVID together with disruption in case finding activities is likely to be responsible for the dramatic drop in both areas. However, physical distancing of COVID had no lasting epidemiological benefit in PEPHans municipalities. High virulent bacilli circulating and incubating in PEPHans municipalities not only nullified any epidemiological benefit but also demonstrably increased the risk of G2D among new cases. Only in non-PEP Maranhão municipalities was the drop in new cases maintained and even accelerated later (aided no doubt by boosted household income thanks to Bolsa Familia cash payments). Newly detected LL cases in São Luís (Maranhão) declined from 52 (2023) to 27 (2025). This favourable outcome in PEP-free places such as São Luís needs to be reinforced by introducing nasal swabs for ALL asymptomatics in case clusters. Then transmission can be ended rapidly, and sustained by periodic mop-up surveillance.
Conclusion:
Human eyes, hands and feet are at stake. The burden of proof is on proponents of short-term chemoprophylaxis to demonstrate that highly conserved and universal macrophage biology is somehow absent in the case of damage to intracellular bacilli by one or a few doses of anti-microbials. That burden is not remotely close to being discharged. The universal macrophage biology is illustrated by a range of epidemiological observations. Short-term chemoprophylaxis not only boosts the risk of new MB HD as shown in the raw data of RCTs, but also is predicted by the biology, and illustrated by convergent epidemiological observations, to be an avoidable risk factor for visible deformity before diagnosis. Brazil and the USA, both scientific powerhouses in macrophage biology and HD research, set good examples to the world by avoiding chemoprophylaxis. Leading groups in countries such as India are also applying science to the protection of their people's eyes, hands and feet.
Short-term chemoprophylaxis was introduced and promoted on the demonstrably false premise that good diagnosis and full free anti-microbial treatment are incapable of reducing transmission. Many places, as listed near the start, showed relatively rapid decline of new MB HD using good diagnosis and full free anti-microbial treatment, without the demonstrable harms of short-term chemoprophylaxis. With semi-quantitative mLAMP on nasal swabs from ALL asymptomatics, all cryptic high-shedders can be made non-infectious within days or weeks. Instead of concentrated viable bacilli being transmitted back and forth indefinitely between persons with genomes predisposing to LL type of HD, elimination of concentrated viable bacilli from a cluster can be achieved in days or weeks.
Is such rapid success undesirable? Is human safety optional?
Safety message for a low‑income person in an endemic area:
Under no circumstances should you accept short‑term chemoprophylaxis for yourself or your loved ones. It can disarm your defender cells, allowing bacilli to replicate and damage your nerves, with risk of visible deformity before diagnosis. Instead, request full examination for signs of HD and a nasal swab to test for high bacillary loads. If either is positive, demand full free treatment with regular check‑ups to protect your nerves. This is also how HD transmission can be ended rapidly.
With all sincerity,
Joel Almeida
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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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