Leprosy Mailing List – December 1, 2023
Ref.: (LML) The impact of SDR PEP (LPEP) on new MB HD cases in Brazil
From: Joel Almeida, Mumbai, India
Dear Pieter and colleagues,
Brazil has rejected SDR PEP (single dose rifampicin post-exposure prophylaxis, also known as LPEP or PEP Hans in Brazil).
Was this decision irrational?
SDR PEP / PEP Hans was implemented in parts of three Brazilian states: Tocantins, Mato Grosso and Pernambuco. A single dose of rifampicin was given to contacts of newly detected HD (leprosy) patients, plus BCG. What followed?
The number of newly detected MB (multibacillary) HD (leprosy) cases increased. This apparently was not what the people of Brazil most desired.
The observed increase in new MB HD in Brazil following SDR PEP is consistent with the outcomes observed in a cluster randomised controlled trial in Bangladesh that measured the effect of SDR PEP on the incidence rate among household contacts and close neighbours of newly diagnosed HD patients. (1) All the included contacts received BCG. 8 to 12 weeks later, a randomly allocated half of these contacts, in clusters, received SDR PEP. The control group consisted of those who did not receive SDR PEP. The outcome specified in the protocol (2) was clinical HD detected among contacts within the first 2 years. The type of HD (MB or PB, paucibacillary) developed by contacts was noted.
In this randomised controlled trial, over three times as many new MB HD cases arose in the SDR PEP group as in the control group (without SDR PEP). Notably, the excess of new MB HD in the SDR PEP group increased between year 1 and year 2. The protocol (2) did not extend beyond 2 years after administration of SDR PEP.
An earlier randomised controlled trial of SDR PEP had not administered a preceding dose of BCG. In that "COLEP" trial, by the end of the double-blind observation period (4 years), the SDR-PEP group yielded 10 new MB HD patients from 38678 person-years of observation.(3) The placebo group yielded 14 new MB HD patients from 38782 person-years of observation. The incidence rate ratio (IRR) in the SDR-PEP group compared to controls is therefore 0.7162 (95% c.i. 0.1632 to 1.612). There is no evidence at all from the COLEP trial of any more than 28% efficacy in preventing MB HD, and even that modest effect cannot be relied on because the confidence interval spreads widely on either side of a zero effect. Incidentally, MB is the type of HD associated with greater risk than PB (paucibacillary) HD of serious adverse consequences for individuals and populations.
Apart from possibly increasing the risk of MB HD, SDR PEP seems likely to increase the following:
a) Stigma & Discrimination - because SDR PEP implementation has been depriving newly diagnosed patients of privacy/confidentiality. Instead in effect, SDR PEP implementation has been misrepresenting all newly diagnosed HD patients as dangerous to contacts. However, the overwhelming majority of actively detected HD patients shed virtually no bacilli, with only 1% to 5% of them showing a BI (bacillary index) greater than 3+ log units.(4) Without positive evidence of densely packed bacilli in nasal smears, it seems unjust to imply or declare that any HD patient is infectious or in any way dangerous to others. Lives can be ruined by violation of confidentiality and misrepresentations.
b) Rifampicin resistance - because SDR PEP implementation risks missing contacts with undiagnosed LL (lepromatous) HD. Undiagnosed persons with "de novo" LL HD can lack prominent signs. Brief chemoprophylaxis is not an adequate substitute for full treatment of LL HD. Further, rifampicin given on its own inevitably kills rifampicin-susceptible HD bacilli and thereby inevitably increases the frequency of rifampicin-resistant mutant bacilli. Such rifampicin resistant mutants are naturally present in every highly bacillated untreated person with LL HD. LL patients unprotected by anti-microbials, either before treatment or after reinfection/recurrence, can shed millions of viable bacilli per day.(5) Unprotected persons with LL HD are the predominant source of concentrated viable bacilli. Therefore, Rifampicin resistance among unprotected persons with LL HD has a disproportionate impact on the entire bacillary population in an endemic area. It tends to shift the entire bacillary population towards drug resistance.
In short, SDR PEP tends to increase Stigma, Discrimination and Rifampicin resistance while failing reliably to reduce new MB HD or possibly even increasing MB HD. In rejecting SDR PEP, Brazil set a world-leading example. Such science-based independence seems important to endemic countries hoping to reduce the incidence rate of HD. What works at the grassroots is not always the same as what the ivory tower prefers.
How can we rapidly and reliably reduce the incidence rate of HD?
Mass multi-drug administration (ROM - rifampicin + ofloxacin + minocycline) in "hot spots" when accompanied by expert skin camps appeared to reduce the incidence rate of HD by up to 40%/year. (6,7) The expert skin camps helped to reduce the risk of missing any LL HD patients. Instead of neglect, LL HD patients received prolonged anti-microbial protection. Elsewhere, even without mass multi-drug administration, simply diagnosing and protecting LL HD patients against (re)infection achieved up to 20%/year decline in the incidence rate of HD. (8-10)
Are we against a 40%/year decline in HD? Otherwise by condoning promotion of SDR PEP we might continue to spread Stigma, Discrimination and Rifampicin resistance along with continuing transmission by missed LL patients including those who received brief chemoprophylaxis instead of full treatment.
A way to rapidly and reliably reduce the incidence rate of MB HD would probably include:
1) Skin camps including teleconsultation with expert clinicians to ensure good examination of peripheral nerves and pinching of skin to rule out the subtle and almost invisible induration that can be the only sign of "de novo" LL HD;
2) Collection of skin smears or at least nasal swabs for microscopy, wherever possible backed by sensitive and specific tests such as qPCR. A highly bacillated "de novo" LL HD patient is likely to show astronomical numbers of acid-fast HD bacilli in nasal smears even before any prominent physical signs appear.(5)
3) Protection of every LL HD patient in endemic areas against (re)infection, by prolonged anti-microbial protection. Fully supervised regimens of post-MDT chemoprophylaxis using potent drugs can shut down nearly all of the ongoing transmission in otherwise well-run programmes.
4) Mass multi-drug administration in "hot spots". The principle of multiple drug use instead of single drug use is well established. Bacilli resistant to one of the drugs are killed by the other drugs.
5) Excellent mobile specialist services (backed by teleconsultation with expert clinicians) to prevent and treat excruciating ENL neuritis and other highly distressing complications of ineffective HD control and inadequate treatment. Without care of people, programmes lose credibility.
Is it a ridiculous idea to learn from well-documented impactful projects at the grassroots? (8-10) Would it be a bad idea to match the 40%/year decline in new HD achievable in hot spots? (6,7)
Joel Almeida
References
1. Richardus R, Alam K, Kundu K et al. Effectiveness of single-dose rifampicin after BCG vaccination to prevent leprosy in close contacts of patients with newly diagnosed leprosy: A cluster randomized controlled trial. International Journal of Infectious Diseases 88 (2019) 65–72.
2. Richardus RA, Alam K, Pahan D et al. The combined effect of chemoprophylaxis with single dose rifampicin and immunoprophylaxis with BCG to prevent leprosy in contacts of newly diagnosed leprosy cases: a cluster randomized controlled trial (MALTALEP study). BMC Infect Dis. 2013 Oct 3;13:456. doi: 10.1186/1471-2334-13-456.
3. Moet FJ, Pahan D, Oskam L et al. Research effectiveness of single dose rifampicin in preventing leprosy in close contacts of patients with newly diagnosed leprosy: cluster randomised controlled trial BMJ 2008;336:761
4. WHO Weekly Epidemiological Record 1998, 73, 153-160
5. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34
6. WORKSHOP ON THE PREVENTION OF LEPROSY, POHNPEI, FEDERATED STATES OF MICRONESIA. 25-27 MAY 1999 sponsored by the Sasakawa Memorial Health Foundation Tokyo, Japan and the Western Pacific Regional Office of the World Health Organization. Int J Lepr, 67 (4) (SUPPLEMENT)
7. Diletto C, Blanc L, Levy L. Leprosy chemoprophylaxis in Micronesia. Lepr Rev. 2000;71(Suppl):S21–3.
8. 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: 8a. Almeida J. Karigiri, India: How transmission rapidly was reduced in a low-income population. LML 29 Oct 2020
9. 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: 9a. Almeida J. Reducing transmission in poor hyperendemic areas - evidence from Uele (DRC). LML 29 Nov 2019
10. 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: 10a. Almeida J. What really happened in Shandong? LML 16 Nov 2019
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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