Leprosy Mailing List – June 23, 2024
Ref.: (LML) Does Rifampicin PEP for household contacts alter the risk of multibacillary HD?
From: Joel Almeida, Mumbai, India
Dear Pieter,
Investigators did a cluster randomised study (1) in 16 villages in Madagascar and 48 villages in Comoros. Villages were randomly assigned to four study arms and inhabitants were screened once a year for HD (leprosy).(2) SDDR-PEP (at least one administration of Rifampicin at or about 20mg/kg considered to be PEP or post-exposure prophylaxis) was used among asymptomatic contacts of incident HD patients. In the control arm, no PEP was provided. In the "household contacts" arm, SDDR-PEP was provided to household contacts of patients. Arm 3 extended SDDR-PEP to anyone living within 100 m. In arm 4, SDDR-PEP was offered to household contacts and to anyone living within 100 m and testing positive to anti-phenolic glycolipid-I.
Was there any difference in the incidence rate of MB (multibacillary) HD in the household contacts arm compared with the control arm? This seems particularly important because Brazil rejected Rifampicin PEP for household contacts after applying it diligently in several Brazilian states and observing a dramatic increase in the risk of MB HD (LML 1 Dec 2023,The impact of SDR PEP (LPEP) on new MB HD cases in Brazil). MB HD has more serious adverse consequences than PB (paucibacillary) HD for the patients and populations of endemic areas.
Observations (2)
In the control arm, 27390 enrolled persons observed for 64423.1 total person-years yielded 27 new MB HD patients, giving an MB HD incidence rate of 4.19/10,000 person-years at risk.
In the "household contacts" arm, 27379 persons observed for 60563.4 total person-years yielded 42 new MB HD patients, giving an MB HD incidence rate of 6.94/10,000 person-years at risk.
The MB HD incidence rate ratio comparing the household contacts arm to the control arm is therefore 1.655 (95% c.i. 1.0203 to 2.6834).
Discussion
Rifampicin PEP given to household contacts increased the risk of MB HD in the "household contact" PEP villages by 65%. This controlled trial in an endemic area was larger than some earlier controlled trials.
There is an important difference between the household contact approach and the blanket approach (where nearly everyone within a village or radius of a new HD patient receives chemoprophylaxis). The household contacts approach reaches a relatively small proportion of unrecognised but highly bacillated "de novo" LL patients. The blanket approach inadvertently reaches nearly all missed but highly bacillated "de novo" LL (lepromatous) patients. Nasal discharges of unprotected LL patients can contain astronomical numbers of viable bacilli even when other signs of HD are minimal. A few doses of potent anti-microbials can temporarily reduce the viability of bacilli in the nasal discharge of "covert" or reinfected LL patients. Therefore the blanket approach is epidemiologically distinct from the household contact approach. Amalgamating outcomes from two distinct approaches can make inferences unreliable.
It is interesting to speculate why anti-mycobacterial drugs for household contacts might increase the risk of MB HD in a village. It seems worth considering the role of environmental (non TB non HD) mycobacteria in helping to protect against MB HD in endemic zones. There might be BCG-like elicitation of non-specific wide-spectrum "trained" innate immunity by environmental mycobacteria (eg., 3-8). If that speculation is even partly correct, then the outcomes of PEP might well depend on two processes with opposing effects: on one hand the killing of atypical environmental mycobacteria that can enhance "trained" immunity even in persons with genomic predisposition (9) to MB HD. On the other hand the killing of HD bacilli in missed and unprotected LL patients. Only in the blanket approach were missed LL patients given at least some anti-microbials, albeit inadvertently and insufficiently. Protective environmental mycobacteria or not, this randomised controlled trial provides evidence that Rifampicin PEP for household contacts in endemic villages substantially increased the risk of MB HD in the said villages.
Brazilian colleagues by rejecting SDR PEP for household contacts despite pressure from some foreign organisations, have protected the Brazilian people from an increased risk of MB HD. So far the world's most rapid epidemiological impacts against HD have come from high-quality professional standards of diagnosis, treatment and care at the grassroots. (10-12) Notably, highly bacillated LL patients were diagnosed competently including through smear examination and their risk of reinfection after treatment was greatly reduced owing to prolonged anti-microbial protection. As much as 16% to 20% annual decline in the incidence rate of MB or LL HD were achieved by such competent grassroots services, even in low-income populations at low geographical latitudes. There are some advantages to liberating colleagues at the grassroots to keep achieving epidemiological and socio-economic impact through action that is science-based, compassionate, just, respectful of human rights and highly effective.
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‐e1026
3. 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
4. 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
5. 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.
6. 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
7. 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
8. 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
9. Zhang F-R, Huang W, Chen S-M, Sun L-D, Liu H, Li Y, et al. Genomewide association study of leprosy. N Engl J Med(2009) 361:2609–18. 10.1056/NEJMoa0903753
10. Norman G, Bhushanam JDRS, Samuel P. Trends in leprosy over 50 years in Gudiyatham Taluk, Vellore, Tamil Nadu. Ind J Lepr 2006. 78(2): 167-185. reviewed and analysed further in: 3a. Almeida J. Karigiri, India: How transmission rapidly was reduced in a low-income population. LML 29 Oct 2020
11. Tonglet R, Pattyn SR, Nsansi BN et al. The reduction of the leprosy endemicity in northeastern Zaire 1975/1989 J.Eur J Epidemiol. 1990 Dec;6(4):404-6 reviewed in: 13a. Almeida J. Reducing transmission in poor hyperendemic areas - evidence from Uele (DRC). LML 29 Nov 2019
12. Li HY, Weng XM, Li T et al. Long-Term Effect of Leprosy Control in Two Prefectures of China, 1955-1993. Int J Lepr Other Mycobact Dis. 1995 Jun;63(2):213-221. reviewed & analysed further in: 14a. Almeida J. What really happened in Shandong? LML 16 Nov 2019
LML - S Deepak, B Naafs, S Noto and P Schreuder
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