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Leprosy Mailing List – October 6, 2019
Ref.: (LML) Single-dose rifampicin PEP increased the risk of MB disease
From: Joel Almeida, Mumbai and London
Dear Pieter and colleagues,
What is the effect of single-dose rifampicin post-exposure prophylaxis (SDR-PEP) among contacts of Hansen's Disease (HD) patients? New evidence is now available, from a randomised controlled trial.
The MALTALEP cluster randomised controlled trial (1) measured the effect of SDR-PEP on the incidence rate among household contacts and close neighbours of newly diagnosed HD patients. 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 disease (MB or PB) developed by contacts was noted. This is useful because MB disease is rarely self-healing and is far more important than PB disease for transmission as well as nerve damage.
The incidence rate of MB disease among contacts with and without SDR-PEP, respectively, can be compared. This has not been done so far, probably owing to an inadvertent oversight.
Outcomes, clinical MB disease
The observed incidence rate of clinical MB disease, comparing SDR-PEP with no SDR-PEP (control group), is shown in the Table below. (One contact developed clinical MB disease before receiving SDR-PEP and is therefore excluded from this table.)
|
| Contacts showing clinical MB disease within 2 years | Person-years at risk (PYAR) | Incidence rate of clinical MB disease /10,000 PYAR
|
| Control group | 3 | 14419 | 2.1 |
| SDR-PEP group | 11 | 14363 | 7.7 |
The Table shows that SDR-PEP increased the incidence rate of MB disease (by 268%).
The calculated incidence rate ratio comparing SDR-PEP to controls is 3.68 (1.026 to 13.197, 95% c.lim.).(3) Further, the incidence rate ratio of MB disease was observed to be much greater during year 2 than during year 1. On this evidence, a subsequent further increase in the incidence rate ratio (over and above 3.68) cannot be excluded. If that occurred, it would compound the disadvantage to contacts receiving SDR-PEP.
Effect of BCG given to contacts
An interesting side calculation also is possible, to estimate roughly the effect of BCG. The trial gave BCG to all included contacts. There was no group without BCG. However, relevant evidence from this same area is available about the incidence rate of MB disease among untreated household and neighbourhood contacts of HD patients. This enables an informed estimate of freshly administered BCG's efficacy in preventing MB disease among contacts.
The incidence rate of all types of clinical HD within 2 years among the household contacts and next-door neighbours in the non-intervention arm of a previous trial in this area was 39.35 per 10,000 PYAR.(4) About 25% of such incident patients in the area show MB disease (5). Therefore, the incidence rate of MB disease among such contacts is about 10 per 10,000 PYAR. By contrast, the observed incidence rate of MB disease in the BCG-only group in this trial is 2 per 10,000 PYAR. Therefore, BCG vaccination of household contacts and close neighbours in this study (1) showed a roughly estimated efficacy of about 80% in preventing MB disease. This magnitude of effect is consistent with previous estimates, and lends support to the established Brazilian policy of BCG vaccination for contacts.
Discussion
SDR-PEP increased the risk of MB disease among those contacts who received SDR-PEP. This might be related to the surprising and counter-intuitive effect of rifampicin on the RNA polymerase of mycobacteria. (6) RNA polymerase or not, this randomised controlled trial shows that SDR-PEP is harmful because it increased the risk of MB disease among those contacts receiving it.
Further, SDR-PEP is monotherapy. Monotherapy selects drug-resistant mutant HD bacilli.(7) The selection of drug-resistant bacilli hastens multiple-drug resistance. That could set back HD control by decades. It is not worth incurring the risk of widespread multiple-drug resistance simply to increase the risk of MB disease among contacts receiving SDR-PEP.
In the light of this new evidence from a randomised controlled trial, it seems advisable and ethical to not promote or use single-dose rifampicin post-exposure prophylaxis (SDR-PEP) in endemic countries.
The two most important reasons why transmission continues are:
a) Missed LL patients in even door-to-door surveys. These missed LL patients can shed up to a billion bacilli per day, including tens of millions of viable bacilli. This situation can be improved by restoring skin smear services and by intensively training front-line staff in hot spots to more reliably recognise the subtle clinical signs of LL disease. Image libraries need to focus more on the subtle cutaneous signs of LL disease.
b) Recurrence of disease (and infectiousness) among LL patients after fixed-duration MDT. This can be improved by post-MDT chemoprophylaxis for all LL patients.
A third reason for continued transmission is created by the use of monotherapy (eg., single-dose rifampicin post-exposure prophylaxis, SDR-PEP) that unnecessarily hastens multiple-drug resistance. It is better to avoid this third reason for transmission altogether, and to focus on remedying the first two reasons. That is how we can succeed.
Joel Almeida
Translations
एकल-खुराक रिफैम्पिसिन पीईपी (SDR-PEP) ने एमबी (MB) रोग के जोखिम को 268% से संपर्कों के बीच बढ़ा दिया। यह एक आरसीटी द्वारा दिखाया गया है, जो सबूत का सबसे मजबूत रूप है। इस नए सबूत से पता चला है कि एसडीआर-पीईपी संपर्कों और आबादी के लिए हानिकारक है। कुछ सबूत भी थे कि बीसीजी घरेलू संपर्कों का टीकाकरण एमबी प्रकार की बीमारी के खिलाफ लगभग 80% सुरक्षा प्रदान करता है।
A dose única de rifampicina PEP (SDR-PEP) aumentou o risco de doença MB entre os contatos em 268%. Isso é demonstrado por um estudo controlado randomizado, que é a forma mais forte de evidência. Essa nova evidência mostrou que SDR-PEP é prejudicial aos contatos e à população. Havia também algumas evidências de que a vacinação BCG de contatos domiciliares oferece cerca de 80% de proteção contra o tipo de doença MB.
La PEP à dose unique à base de rifampicine (SDR-PEP) a augmenté le risque de maladie à MB de 268%. Ceci est démontré par un essai contrôlé randomisé, qui est la forme de preuve la plus solide. Cette nouvelle preuve a montré que le SDR-PEP est nocif pour les contacts et la population. On disposait de certaines preuves selon lesquelles la vaccination par le BCG des contacts familiaux offre environ 80% de protection contre le type de maladie MB.
La PEP de dosis única basada en rifampicina (SDR-PEP) aumentó el riesgo de enfermedad MB en un 268%. Esto se demuestra mediante un ensayo controlado aleatorio, que es la forma más fuerte de evidencia. Esta nueva evidencia ha demostrado que SDR-PEP es perjudicial para los contactos y la población. Se disponía de cierta evidencia de que la vacuna BCG de los contactos domésticos ofrece aproximadamente un 80% de protección contra la enfermedad tipo MB.
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. Int J Infect Dis. 2019 Sep 6. pii: S1201-9712(19)30365-0. doi: 10.1016/j.ijid.2019.08.035. [Epub ahead of print]
2. Richardus RA1, 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. Confidence interval of Incidence Rate Ratio
4. Moet FJ, Pahan D, Oskam L, et al. Effectiveness of single dose rifampicin in preventing leprosy in close contacts of patients with newly diagnosed leprosy: cluster randomised controlled trial. BMJ 2008;336(7647):761-4. doi: 10.1136/bmj.39500.885752.BE
5. Butlin CR, Nicholls P, Bowers B. Outcome of late healthy household contact examinations in leprosy-affected households in Bangladesh. Lepr Rev 2019: 90, 305–320.
6. Zhu JH, Wang BW, Pan M et al. Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription. Nature Communications 2018; 9: 4218.Published online 2018 Oct 11. doi: 10.1038/s41467-018-06667-3
7. Benjak A, Avanzi C, Singh P et al. Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae. Nature Communications volume 9, Article number: 352 (2018)
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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