Leprosy Mailing List – April 1, 2020
Ref.: (LML) Multi-drug chemoprophylaxis is less harmful than SDR-PEP
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
The evidence shows why SDR-PEP is harmful, and why replacing it with multi-drug chemoprophylaxis is not only the right and ethical thing to do, but also the smart thing to do microbiologically and epidemiologically.
Joel Almeida
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Introduction & summary
Chemoprophylaxis with a multi-drug combination (rifampicin+ofloxacin+minocycline) was used in the Federated States of Micronesia in the late 1990s, supported by WHO and the Sasakawa Health Foundation. This had good immediate outcomes. (1) HD returned after a lull. (1b) Since then, the advantages of multi-drug use have been somewhat ignored, as also the harms accompanying single drug use. Evidence shows that the harms accompanying SDR-PEP (single-dose rifampicin post-exposure prophylaxis) may be summarised under two heads:
A. Selection of rifampicin-resistant mutant bacilli, and
B. Increased risk of new MB (multibacillary) HD (Hansen's disease) among contacts.
The first point, selection of drug-resistant mutant bacilli, could compromise HD control for decades. That is especially true because rifampicin is unrivalled for bactericidal effect (apart from rifapentine). The second point, increased risk of new MB disease, harms individual recipients and also works against HD control. Multi-drug chemoprophylaxis avoids most of the evidenced harms that accompany SDR-PEP.
Further, the only tried and tested approach so far, for interrupting transmission relatively rapidly, has been prolonged anti-microbial protection for LL patients (as illustrated at the end). Rifampicin-resistant bacilli selected by SDR-PEP could disable this critical requirement for near-zero transmission. Then HD is likely to continue damaging people in endemic countries, for decades more. It seems advisable, on grounds of ethics and human rights, to cease promoting or using SDR-PEP in endemic countries. Multi-drug chemoprophylaxis gets rid of the harms of SDR-PEP but retains any hoped-for benefits.
The evidence is discussed below.
A. SDR-PEP and rifampicin resistance
Fig. 1. Rifampicin-resistant bacilli increase in frequency among surviving bacilli during anti-microbial treatment. The inclusion of other drugs helps to kill rifampicin-resistant bacilli in due course. (2)
A single dose of rifampicin kills about 90% of rifampicin-susceptible bacilli. That is evidenced by serial dilution experiments in the mouse foot-pad, comparing bacillary populations before and after a single dose of rifampicin. (2) Therefore, the frequency of rifampicin-resistant mutant bacilli among the surviving bacilli increases by about 10 times after a single dose of rifampicin. This is an inescapable mathematical fact, since {n/0.1} is ten times greater than {n/1}.
The mouse foot-pad test has long served as the gold standard of detecting bacilli that show drug-resistant phenotypes. It is useful to understand some details of the mouse foot-pad test. It uses an inoculum of about 5x10^3 bacilli from a skin biopsy. Such an inoculum from an untreated person with LL HD includes about 5x10^2 viable bacilli. (3) However, after 90% bactericide by a single dose of rifampicin, such an inoculum for the mouse foot-pad test is expected to include only 5x10^1 = 50 viable bacilli. Therefore, until the frequency of rifampicin-resistant bacilli reaches 1 in 50 viable bacilli, the mouse foot-pad test generally will yield a false negative result for rifampicin-resistant bacilli. Complacency based on such a false negative test would be a serious error.
A few LL patients in the 1980s who had many years of dapsone monotherapy were given a single large dose of rifampicin (1500 mg). Some of them showed recurrence of LL HD. The mouse foot-pad inoculum from such a patient with recurrence might contain as many as 5 x 10^2 viable bacilli. Even this can give a false negative test for rifampicin resistant-bacilli. That is because the frequency of rifampicin-resistant mutant bacilli in rifampicin-naive bacillary populations is probably about 10^-6, and at most 10^-4. A single dose of rifampicin with 90% bactericide would increase this, at most, to 10^-5 to 10^-3. This would still be less than the 1 in 500 frequency required for detection of rifampicin-resistant bacilli in the mouse foot-pad test. Accordingly, a false negative mouse foot-pad test for rifampicin-resistant bacilli is likely.
Complacency about SDR-PEP selecting rifampicin-resistant mutant bacilli is contrary to firm evidence of bactericide by rifampicin, using quantitative serial dilution methods. Complacency arises from unevidenced assertions, or false negative mouse foot-pad tests as discussed above.
The selection of rifampicin-resistant mutant bacilli by SDR-PEP is especially likely among missed LLp (de novo LL) patients who can show few or no signs of HD despite harbouring and shedding astronomical numbers of bacilli. (4, 4a) With multi-drug chemoprophylaxis, other drugs can inhibit rifampicin-resistant bacilli. Accordingly, multi-drug chemoprophylaxis (unlike SDR-PEP) is consistent with the high standards of science, ethics and human rights on which our community prides itself.
For those here not from a biological background, an analogy might help visualise the main harm from SDR-PEP.
Figure 2. (for readers not from a biological background:) Rifampicin-resistant bacilli selected by SDR-PEP are like accumulating rocks hidden under water. SDR-PEP could wreck the ship of HD control. We cannot afford to remain blindfolded to relevant details as we steer the ship. As we pay increasing attention to a wider range of evidence and more voices (including from scientists in endemic countries), we can make the necessary mid-course corrections and improvements. Then the people of endemic countries will be protected from unnecessary harm, and enjoy improved prospects of near-zero transmission, near-zero disability and declining stigma.
B. SDR-PEP increased the risk of MB HD in a randomised controlled trial
Fig. 3. (from table 5 of ref 5) SDR-PEP in this RCT (randomised controlled trial) increased the risk of MB disease by 267% (incidence rate ratio 3.67, 95% c.i. 1.026 to 13.20). BCG had been given to both groups 8 to 12 weeks earlier. Follow-up was discontinued at 2 years.
The excess of new MB patients in the SDR-PEP group increased over time, and was greater in year 2 than in year 1. This suggests that observation beyond 2 years might well have revealed an even greater excess of MB patients in the SDR-PEP group. The important observation is that SDR-PEP in this RCT increased the risk of MB disease by 267%.
The increase in the risk of MB disease might be related to the recent demonstration, using other mycobacteria, that rifampicin up to a certain concentration preferentially inhibited one of the two rpoB promoters within the bacilli. This allowed increased rpoB expression from the other rpoB promoter, thus triggering bacillary growth. (6)
The increase in the risk of MB disease might also be partly because the 8 to 12 week interval between BCG and SDR-PEP was insufficient to spare BCG bacilli. The incidence rate of MB HD in historical contacts in this area of Bangladesh, without BCG, is calculated to be at least 4.5/10,000 person-years at risk (PYAR) (7). Whereas in BCG (re)vaccinated contacts it is calculated to be about 2/10,000 PYAR (5). BCG therefore apparently had a greater than 50% protective effect against MB HD in this population. In Brazil, BCG among contacts can be calculated to have had a greater than 70% protective effect against MB HD.(8) However, the possible killing of BCG bacilli by SDR-PEP might not be sufficient to explain the excess risk, given the 8 to 12 week interval between BCG and rifampicin in this trial,(5) and the magnitude of excess of MB HD in the SDR-PEP group (267%).
Whether or not these two explanations above apply, the increased risk of MB disease was observed in the SDR-PEP group. The solution would be to use multi-drug chemoprophylaxis instead of SDR-PEP, and to give it before BCG.
Incidentally, live mycobacteria such as BCG are known to evoke "trained immunity", a non-specific defence against a wide range of pathological cells. Trained immunity relies on a kind of innate immunity (involving macrophages, monocytes, natural killer cells etc). (9) That is why BCG is among the candidate vaccines for protecting the general population against SARS-CoV-2 (COVID-19's causative organism) and similar viruses with pandemic potential. Brazilian policy is to give BCG (re)vaccination to all contacts of newly diagnosed HD patients.
Discussion
A single dose of rifampicin kills 90% of rifampicin-susceptible bacilli and therefore produces a 10-fold increase in the frequency of rifampicin-resistant mutants among surviving bacilli. Further, SDR-PEP in an RCT (randomised controlled trial) increased the risk of MB HD among contacts by 267%. Therefore, it seems advisable to avoid SDR-PEP, with its accompanying harms, on grounds of ethics and human rights. Multi-drug chemoprophylaxis instead of SDR-PEP, and given before BCG, offers any hoped-for advantages of chemoprophylaxis without the evidenced harms that accompany SDR-PEP.
The replacement of SDR-PEP by multi-drugs will also help keep alive our chances of a rapid decline of HD as achieved in Shandong, China (10) and Uele, DR Congo (11). Those rapid declines (up to 20%/year) occurred despite relatively low per capita GDP, relying on prolonged anti-microbial protection for LL patients. Drug-resistant mutant bacilli selected by SDR-PEP could block the path to such success. Then, HD unnecessarily could keep disfiguring and oppressing generations of people in endemic countries.
We might be tempted to cling to mistaken claims and harmful interventions such as SDR-PEP, owing to conflicts of interest. However, any hoped-for financial advantage will soon evaporate, leaving the people of endemic countries with a boosted frequency of rifampicin-resistant bacilli. We have already seen HD finances evaporate because of spurious boasts about HD, resulting in the destruction of HD services and a haemorrhage of talent. We cannot afford to cling to any more mistaken claims, because the price is measured in the nerves, limbs, eyes, minds, livelihoods, relationships and rights of vulnerable people in endemic countries.
Mahatma Gandhi and Nelson Mandela were well acquainted with conflicts of interest among the privileged. This did not stop them from pursuing the best interests of their people. Many of those at risk of being given SDR-PEP are illiterate and poor, but they are entitled to human and legal rights.
Conclusions
It seems unethical to promote or use SDR-PEP in endemic countries. Public education can use simple messages.
For affluent countries:
SDR-PEP selects drug-resistant bacilli. It also increased the risk of MB HD (more dangerous type of leprosy) by 267% in a careful trial.
Help protect the people of endemic countries against SDR-PEP. Help them get multi-drug chemoprophylaxis instead.
For endemic countries:
Protect yourself by rejecting SDR-PEP. This will also help protect your family, your community and your country from drug-resistant HD (leprosy). Demand multi-drug combinations instead.
Fig 4. A rapid decline in new HD patients was achieved in Shandong (lower line in the figure) using prolonged anti-microbial protection for LL patients among others.(10) This led to near-zero transmission, probably because it shut down a hugely important source of concentrated viable bacilli, namely LLp patients with recurrent HD. Instead of promoting demonstrably harmful interventions such as SDR-PEP, we could emulate proven success and aim to match it.
An example protocol for safe, rapid interruption of transmission has been discussed here previously. Esteemed colleagues can adapt and improve it for use in their own areas. Any organisation which implements such a science-based protocol and produces a rapid decline of MB HD will find the whole world rushing to congratulate and support them. The sooner we replace SDR-PEP with multi-drug chemoprophylaxis, the less harm we will cause to vulnerable people in endemic countries and the sooner we will achieve near-zero transmission, near-zero disability, near-zero stigma and near-zero injustice.
This is an opportunity to succeed in rapidly reducing the incidence rate of HD by upholding the high standards of ethics and human rights of which our community is proud. The evidence shows that replacing SDR-PEP with multi-drug chemoprophylaxis is not only the right and ethical thing to do, but also the smart thing to do.
Translations
एसडीआर-पैप को अस्वीकार करके अपने और अपने परिवार की रक्षा करें। एसडीआर-पैप स्वस्थ लोगों को पेश किया जाने वाला लाल कैप्सूल है। उन्हें अस्वीकार करें। इसके बजाय बहु-दवा संयोजन की मांग करें। एसडीआर-पैप को अस्वीकार करने से न केवल आपके परिवार, बल्किआपके समुदाय और आपके देश को मुश्किल-से-ठीक होने वाली दवा प्रतिरोधी कुष्ठ रोग से सुरक्षा मिलेगी।
Proteja você e sua família rejeitando o SDR-PEP. SDR-PEP são as cápsulas vermelhas oferecidas a pessoas saudáveis. Rejeite-os. Exija combinações de múltiplas drogas. A rejeição do SDR-PEP protegerá não apenas sua família, mas também sua comunidade e seu país contra a hanseníase resistente a medicamentos, difícil de curar.
Lindungi diri Anda dan keluarga Anda dengan menolak SDR-PEP. SDR-PEP adalah kapsul merah yang ditawarkan kepada orang sehat. Tolak mereka. Minta kombinasi multi-obat sebagai gantinya. Menolak SDR-PEP tidak hanya akan melindungi keluarga Anda, tetapi juga komunitas dan negara Anda dari kusta yang kebal terhadap obat-obatan dan sulit disembuhkan.
Protégez-vous et votre famille en rejetant le SDR-PEP. SDR-PEP est les capsules rouges proposées aux personnes en bonne santé. Rejette-les. Exigez plutôt des combinaisons de plusieurs médicaments. Le rejet du SDR-PEP protégera non seulement votre famille, mais aussi votre communauté et votre pays contre la lèpre résistante aux médicaments, difficile à guérir.
Protéjase usted y su familia rechazando SDR-PEP. SDR-PEP son las cápsulas rojas que se ofrecen a personas sanas. Rechazarlos. Exija combinaciones de múltiples drogas en su lugar. Rechazar SDR-PEP protegerá no solo a su familia, sino también a su comunidad y su país contra la lepra resistente a los medicamentos que es difícil de curar.
References
1. 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)
1b. WHO Weekly Epidemiological Record. No. 34, 2005, 80, 289–296
2. Almeida, JG. A Quantitative Basis for Sustainable Anti-Mycobacterium leprae Chemotherapy in Leprosy Control Programs. Int J Lepr (1992) 60(2):255-268.
3. Levy L. Treatment Failure in Leprosy. Int J Lepr. (1976) 44: 177-82.
4. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
5. 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.
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. 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 doi: https://doi.org/10.1136/bmj.39500.885752.BE
8. Düppre NC, Camacho LAB, da Cunha SS et al. Effectiveness of BCG Vaccination Among Leprosy Contacts: A Cohort Study. Trans R Soc Trop Med Hyg (Jul 2008), 102 (7): 631-8
9. Arts RJW, Moorlag SJCFM, Novakovic B et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host & Microbe, JANUARY 10, 2018, 23(1) 89-100.
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.
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.
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LML - S Deepak, B Naafs, S Noto and P Schreuder
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