Leprosy Mailing List – July 30, 2019
Ref.: (LML) Drug costs and impact of post-MDT chemoprophylaxis for LL patients
From: Joel Almeida, Mumbai and London
Dear Pieter,
Thanks to Dr. Gelber (LML, July 26, 2019) for sharing his well-informed understanding on this topic. He has been responsible for major advances in chemotherapy, including the introduction of minocycline. We can be grateful to be standing on the shoulders of giants. Prof. Isabela Goulart (Brazil) had earlier provided detailed research findings and well-reasoned suggestions. Dr. Kawuma (Uganda) and several others had earlier also shared their well-reasoned views. All people of goodwill from across the world have been coming together to fight our common enemy: the potentially devastating bacilli. Thanks to LML, we have an open platform for building rapidly on one another's insights. "How can you get the best ideas and have the ideas, and not the hierarchies, win?" asked Dr. Vas Narasimhan in an interview. LML fosters such a healthy community of science, enabling constructive and rapid progress. Anybody can put their shoulder to the wheel and advance our common cause. The validity and utility of ideas matters much more than the identity of those making contributions.
Those from a non-biological background might find an analogy useful in understanding post-MDT chemoprophylaxis. Imagine Hansen's Disease (HD) as a fire. Imagine polar LL (LLp) patients as perspiring kerosene during their whole life, owing to genetically-determined anergy. Would we send these inflammable individuals unprotected to face fire again? Of course not. We would ensure their protection before sending them out again.
That's why it is necessary to provide post-MDT chemoprophylaxis to LLp patients in endemic areas. It is like "fire-proofing" for innately "inflammable" individuals. Our challenge is to ensure that one highly "inflammable" LLp patient never "sets fire" to another such patient, directly or indirectly. That can be powerfully effective. That's how the "fire" starts to die out. In epidemiological terms, that can reduce the reproductive ratio of infected LLp patients to below one. That's how Shandong wiped out the disease, achieving near-zero transmission.
Evidence keeps mounting that progressive forms of HD are like a distinct disease. They differ from self-limiting forms in terms of genetics and pathophysiology. (1-4) Our efforts need constantly to be updated in the light of such accumulating evidence.
Further, untreated LLp patients are also the most likely to shed high concentrations of viable bacilli, as many as a billion bacilli per day including tens of millions of viable bacilli. (5) Without post-MDT chemoprophylaxis, they are forced unknowingly to spread the "fire" once they suffer relapse or re-infection. No other untreated sources, apart from armadillos, develop such high concentrations of viable bacilli.
LL patients are also the most likely to have suffered visible deformity, and they remain at greatest risk of further nerve damage. Competent case management for them involves not just post-MDT chemoprophylaxis but also comprehensive services for nerve protection, rehabilitation and inclusion. These patients have a huge job in addition to contributing their individual gifts to society. That job is to fight the bacilli on everyone's behalf. They might not realise how important that job is. We realise, because we understand the underlying biology. With proper epidemiological understanding, these persons can be recognised and treated as VIPs. Monthly chemoprophylaxis, as part of comprehensive case management services, is useful because it facilitates regular ingestion of drugs. Monthly contact with a designated helper can help affected persons with visible deformity also to access services for nerve protection, rehabilitation and inclusion.
What about BL patients? They too can have post-MDT chemoprophylaxis and comprehensive case management services, although they tend to shed far fewer viable bacilli than do LLp patients. (5)
What about endemic areas where skin smear and lab services have been neglected or shut down? While we work to restore those services, we could rely on physical signs. All those with widely and symmetrically distributed signs of HD could be regarded as eligible for post-MDT chemoprophylaxis. It is better to be cautious. Eventually, as investment increases, we can restore quality-controlled laboratory services in all endemic areas.
We need no longer abandon LLp patients to the bacilli, after MDT. We now know that recurrence of disease allows concentrated bacilli to spread despite all our other worthy efforts. Post-MDT chemoprophylaxis, for all LL patients in endemic areas, can reduce the cumulative recurrence rate of disease among LLp patients from as high as 75% to near 0%. Otherwise, all our good work with other interventions can be undone. Neglect of LL patients after MDT carries a heavy price not only for the individuals but also for society.
Post-MDT chemoprophylaxis for LL patients is the only intervention, apart from MDT itself, which interrupts transmission at source. Once we add post-MDT chemoprophylaxis for all LL patients in endemic areas, and prevent stock-outs of MDT in peripheral health centres, we have a realistic chance of wiping out this devastating disease (at least from continents without armadillos). It is our best hope of matching Shandong's demonstrable victory. A 20%/year decline in incidence rate, leading to zero transmission, would transform endemic countries. Think of billions of children, generations to come, freed from the threat of this devastating disease. We can achieve this if we act before multiple-drug resistant (MDR) bacilli take over.
Let's act before it's too late.
Joel Almeida
Translations
वे लोग जो जीवविज्ञानी नहीं हैं, वे एक सादृश्य उपयोगी पा सकते हैं। आग के रूप में हैनसेन की बीमारी की कल्पना करें। कल्पना कीजिए कि एलएल रोगियों को जीवन भर केरोसिन पसीना आता है। क्या हम इन ज्वलनशील व्यक्तियों को असुरक्षित रूप से आग में भेज देंगे? बिलकूल नही। आग में लौटने से पहले हम उन्हें सुरक्षा उपकरण देंगे।
इसलिए नए रोगियों की अधिक संख्या वाले क्षेत्रों में एलएल रोगियों को पोस्ट-एमडीटी केमोप्रोफिलैक्सिस प्रदान करना आवश्यक है। यह "ज्वलनशील" लोगों के लिए "फायर-प्रूफिंग" जैसा है।
यह सुरक्षा शांडोंग की जीत की बराबरी करने का हमारा सबसे अच्छा मौका है। इसके बिना, रोग में गिरावट 20% प्रति वर्ष के बजाय प्रति वर्ष 10% से कम होने की संभावना है। दवा प्रतिरोधी बेसिली हर जगह फैलने से पहले, शून्य संचरण प्राप्त करना आवश्यक है। हमें जल्दी से काम करने की जरूरत है।
Aquelas pessoas que não são biólogos podem ser ajudadas por uma analogia. Imagine a hanseníase como um incêndio. Imagine pacientes com LL suando querosene devido à sua genética. Será que vamos enviar essas pessoas inflamáveis desprotegidas para o fogo? Claro que não. Nós lhes daremos equipamentos de segurança antes que retornem ao fogo.
Portanto, a quimioprofilaxia pós-PQT deve ser fornecida a pacientes com LL em áreas endêmicas. Isto é como "prova de fogo" para pessoas "inflamáveis".
A quimioprofilaxia pós-PQT fecha a lacuna principal em nossa abordagem e nos permite alcançar uma transmissão quase zero como Shandong. Sem isso, o declínio da doença provavelmente será inferior a 10% ao ano, em vez de 20% ao ano. Antes que os bacilos resistentes aos medicamentos se espalhem por toda parte, precisamos interromper a transmissão. Precisamos agir rapidamente.
Les personnes qui ne sont pas biologistes peuvent être aidées par une analogie. Imaginez Hanseniasis comme un feu. Imaginez des patients LL transpirant du kérosène en raison de leur génétique. Allons-nous envoyer ces personnes inflammables non protégées dans le feu? Bien sûr que non. Nous leur donnerons du matériel de sécurité avant leur retour au feu.
Par conséquent, une chimioprophylaxie post-PCT doit être fournie aux patients LL des zones d'endémie. Cela ressemble à une "résistance au feu" pour des personnes "inflammables".
La chimioprophylaxie post-PCT comble le principal problème de notre approche et nous permet d'obtenir une transmission presque nulle, comme dans le Shandong. Sans cela, le recul de la maladie serait probablement inférieur à 10% par an au lieu de 20% par an. Avant que le bacille pharmacorésistant ne se répande partout, nous devons interrompre la transmission. Nous devons agir rapidement.
Aquellas personas que no son biólogos pueden ser ayudadas por una analogía. Imagina la Hanseniasis como un fuego. Imagina a los pacientes con LL sudando queroseno debido a su genética. ¿Enviaremos a estas personas inflamables desprotegidas al fuego? Por supuesto no. Les daremos equipo de seguridad antes de que vuelvan al fuego.
Por lo tanto, debe proporcionarse quimioprofilaxis post-PCT a pacientes con LL en áreas endémicas. Esto es como "prueba de fuego" para personas "inflamables".
La quimioprofilaxis después de PCT cierra la brecha principal en nuestro enfoque y nos permite lograr una transmisión de casi cero como Shandong. Sin ella, es probable que la disminución de la enfermedad sea inferior al 10% anual en lugar del 20% anual. Antes de que los bacilos resistentes a los medicamentos se diseminen por todas partes, debemos interrumpir la transmisión. Tenemos que actuar con rapidez.
References
1) Andrade PR, Mehta M, Lu J et al. The cell fate regulator NUPR1 is induced by Mycobacterium leprae via type I interferon in human leprosy. PLOS NTD, July 25, 2019 https://doi.org/10.1371/journal.pntd.0007589
2) Gaschignard J, Grant AV, Thuc NV et al. Pauci- and Multibacillary Leprosy: Two Distinct, Genetically Neglected Diseases. PLoS Negl Trop Dis. 2016 May 24;10(5):e0004345. doi: 10.1371/journal.pntd.0004345
3) Wang N, Wang Z, Wang C et al. Prediction of leprosy in the Chinese population based on a weighted genetic risk score. PLoS Negl Trop Dis. 2018 Sep 19;12(9):e0006789. doi: 10.1371/journal.pntd.0006789.
4) Palermo ML, Pagliari C, Trindade MA et al. Increased expression of regulatory T cells and down-regulatory molecules in lepromatous leprosy. Am J Trop Med Hyg. 2012 May;86(5):878-83. doi: 10.4269/ajtmh.2012.12-0088.
5) Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
LML - S Deepak, B Naafs, S Noto and P Schreuder
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