Leprosy Mailing List – July 28, 2024
Ref.: (LML) Does Rifampicin PEP for household contacts alter the risk of multibacillary HD?
From: Joel Almeida, Mumbai, India
Dear Pieter and colleagues,
Thanks to Epco Hasker for his comments. (Ref.: (LML), 24 July 2024).
He rightly indicates that the comparison of arm 2 (household SDDR PEP) with arm 1 (non PEP) showed an excess of new MB HD cases in arm 2. This comparison was between the ENTIRE arm 2 and the ENTIRE arm 1 populations. No sub-group involved. It is a comparison explicitly described in the published protocol: "Incidence rate ratios calculated between the comparator arm 1 and each of the intervention arms will constitute the primary outcome". (1) The said analysis was inexplicably omitted by Hasker et al, but it reveals a 65% excess of new MB HD in the SDDR PEP household contacts arm (IRR 1.655, 95% c.i. 1.0203 to 2.6834).
Beyond that Epco Hasker and associates did several things that were not pre-defined in the protocol analysis. Such post-hoc analysis tends to be unreliable for superiority trials because post-hoc regrouping or exclusions or re-allocation of subjects can mislead even the best-intentioned analyst. This danger is heightened when the trial data are not shared openly. Further, Poisson regression assumes that the dependent variable has a Poisson distribution. This distribution expresses the probability that a given number of events will occur in a fixed interval, assuming that these events occur at a known constant rate on average and that each event is independent of the others. This assumption might not be safe in the present context because incident cases can be the source of further incident cases.
The most remarkable part of the Hasker et al report is the section on adverse outcomes. (2) "We did not conduct active follow-up for adverse events. Probably there were no serious adverse events since none were reported." However, the Helsinki Declaration requires that the protocol include "provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study." Simply closing one's eyes to adverse events is not sufficient. We now know that the LPEP study in DNH showed a vast boost of G2D (visible deformity) following SDR-PEP for household contacts, neighbours and social contacts. A similar boost in G2D / visible deformity cannot be excluded in the PEOPLE trial run by Hasker et al. This is what people need to know before they give informed consent to HD chemoprophylaxis: their risk of G2D (visible deformity) is likely to be boosted greatly.
Hasker asks why those who did not receive SDDR PEP might have developed MB HD. MB HD is caused by M. leprae, above all the concentrated viable bacilli shed by undiagnosed or reinfected LL (lepromatous) HD patients. The published protocol stated, "Leprosy diagnosis will be clinical, based on the presence of three cardinal signs: patch with loss of sensation, enlarged peripheral nerves and/or slit-skin smear (SSS) positive for acid fast bacilli. All leprosy cases diagnosed will be verified by experienced leprosy national control program staff." This is unpromising for diagnosis of LL HD patients, because the first two of the three listed cardinal signs are often absent from new "de novo" LL HD patients. Wherever diagnosis of LL HD is unreliable, HD will spread. Hasker et al could consider improving their skills, so as to miss fewer "de novo" LL patients.
We are still learning about mycobacteria, anti-mycobacterials, immune responses, etc. The biology shows surprising twists. More twists are sure to emerge. The twists extend beyond the release of TLR-9 ligands from M. leprae by the use of anti-mycobacterial drugs and the consequent cytokines storm of ENL.(3) The people of Comoros, like those in DNH, periodically go barefoot and might well be co-infected by protective environmental (non TB non HD) mycobacteria that are susceptible to anti-M.leprae drugs. Killing such protective mycobacteria by HD chemoprophylaxis would be like knocking out the BCG-style natural wide-spectrum vaccination (5-10) which possibly had helped to limit MB HD and G2D / visible deformity among the Comorians.
There is more. For example, rifampicin plasma concentrations decline rapidly following a single dose. This exposes M. leprae for a significant period to relatively low concentrations of rifampicin. Mycobacterial tolerance can be provoked by exposure to inhibitors of RNA polymerase such as rifampicin. RNA polymerase-specific phenotypic resistance/tolerance is demonstrably triggered by the transient increased expression of the beta subunit of RNA polymerase (rpoB) which in turn is due to divergent effects of rifampicin on two rpoB-rpoC promoters. Usually expression from Promoter I inhibits expression from Promoter II. Rifampicin preferentially inhibits Promoter I allowing maximal rpoB expression and mycobacterial growth. In one type of rpoB-accumulating mycobacteria (labelled Type V), rifampicin is followed not by inhibition but by division of cells and growth.(11) Whether or not this partly or wholly explains the "intense transmission" reported from places such as Alta Floresta (Mato Grosso, Brazil) following PEP RDU / LPEP / SDR PEP, we cannot exclude an increase in the virulence of M. leprae arising from phenotypic changes induced by rifampicin.
Whatever the underlying biology, the likely impact on those who receive HD chemoprophylaxis and then develop G2D (visible deformity) is hastened destitution. That in itself is an additional risk factor for HD.
Worryingly, exposure of mycobacteria to rifampicin combined with other drugs (eg., isoniazid) still caused up-regulation of rpoB.(11) Therefore the unintended harms of HD chemoprophylaxis might prove surprisingly hard to shake off. Other antimycobacterials too might hold surprises. Human beings need to be protected even (or especially) if they are on low incomes in endemic countries.
Thanks to Epco Hasker for his questions. Nearly all of the most knowledgeable HD experts in the world are on LML, and nearly all are duly respectful of human rights and ethics. Are Hasker and associates opposed to respect for the patients and populations of endemic areas? Surely not.
With all sincerity,
Joel Almeida
References
1. Ortuno-Gutierrez N, Younoussa A, Randrianantoandro A, et al.Protocol, rationale and design of PEOPLE (Post ExpOsure Prophylaxis for LEprosy in the Comoros and Madagascar): a cluster randomized trial on effectiveness of different modalities of implementation of post-exposure prophylaxis of leprosy contacts. BMC Infect Dis 2019; 19: 1033.
2. E Hasker, Y Assoumani, A Randrianantoandro et al. Post-exposure prophylaxis in leprosy (PEOPLE): a cluster randomised trial. The Lancet Global health, 2024, 12(6), e1017‐e102614.
3. Dias AA, Silva CO, Santos JPS, Batista-Silva LR, Acosta CCD, Fontes ANB, et al. DNA sensing via TLR-9 constitutes a major innate immunity pathway activated during erythema nodosum leprosum. J Immunol(2016) 197:1905–13. 10.4049/jimmunol.1600042
5. Pinheiro RO, Schmitz V, de Andrade Silva BJ et al. Innate Immune Responses in Leprosy. Front Immunol. 2018; 9: 518. Published online 2018 Mar 28. doi: 10.3389/fimmu.2018.00518
6. Kleinnijenhuis J,Quintin J, Preijers F et al. Bacille Calmette-Guérin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012 Oct 23; 109(43): 17537–17542. Published online 2012 Sep 17. doi: 10.1073/pnas.1202870109
7. Fine PEM, Floyd S, Stanford J et al. Environmental mycobacteria in northern Malawi: implications for the epidemiology of tuberculosis and leprosy. Epidemiol Infect, 2001; 126: 379–387.
8. Denise L, Faustman AL, Hostetter ER. Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes. Cell Rep Med. 2022 Sep 20; 3(9): 100728. Published online 2022 Aug 15. doi: 10.1016/j.xcrm.2022.100728
9. Zhou,J, Jingzhu Lv, Carlson C et al. Trained immunity contributes to the prevention of Mycobacterium tuberculosis infection, a novel role of autophagy. Emerg Microbes Infect. 2021; 10(1): 578–588. Published online 2021 Mar 30. doi: 10.1080/22221751.2021.1899771
10. Jensen KJ, Larsen N, Biering-Sørensen S.Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial J Infect Dis. 2015 Mar 15; 211(6): 956–967. Published online 2014 Sep 9. doi: 10.1093/infdis/jiu508
11. Zhu J-H, Wang B-W, Pan M. Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription Nature Commun. 2018 Oct 11;9(1):4218. doi: 10.1038/s41467-018-06667-3.
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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