Ref.: (LML) Single-dose rifampicin PEP increased the risk of MB disease
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
Thanks to Mr. Warne for his comment of October 9, 2019 about my earlier LML contribution on this subject. I shone a spotlight on a crucial part of the MALTALEP report 2019 (1). However, that report itself displays the substance.
The substance of the unexpected finding
The MALTALEP report 2019 (1) of a randomised controlled trial itself shows that in the SDR-PEP group vs the control group there was an excess of contacts who developed MB disease within two years. This is fact. It is displayed in the report. It is not open to dispute. Mr. Warne is right in taking this fact very seriously, although the magnitude of the risk might not have been grasped fully. That is discussed later.
Biological context
What could be the biological explanation for the excess of MB cases in the SDR-treated group? In a recent demonstration using other mycobacteria, 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.(2) Whether or not this explains the observed excess of MB signs in the SDR-PEP group, the excess was observed and reported. (1) That fact cannot be wished away.
Further, single-dose rifampicin PEP was already considered a potential threat to HD control because it is monotherapy. Monotherapy selects drug-resistant HD bacilli.(3) This would happen especially in hard-to-diagnose and missed LL patients wrongly classed as disease-free contacts and given SDR-PEP. Even skilled and experienced clinicians can miss the subtle signs of LL disease, unless they do a skin smear examination. Multi-purpose primary care workers are almost certain to make this mistake. Such a missed LL patient can shed a billion bacilli per day, now including a higher frequency of drug-resistant bacilli owing to SDR-PEP. Drug-resistance not only can make individual patients difficult to cure, but also could put HD control completely out of our reach. A recent report about multiple-drug resistant HD from Brazil shows how careful we need to be.(4) Therefore, the indispensable precaution always is to use a balanced combination of bactericidal drugs, instead of SDR.
Accordingly, the underlying biology shows how SDR-PEP poses a threat not just to those who receive it, but also to HD control.
The magnitude of risk
The major risk from SDR-PEP is the selection of drug-resistant HD bacilli. That is not all.
In about 7000 contacts given SDR-PEP, the MALTALEP RCT report shows that 8 additional contacts developed MB disease within about 2 years, compared to the control group.(1) These 8 additional contacts would otherwise have remained healthy. If a large endemic region scaled up SDR-PEP and gave it to 10 million contacts per year, about 11,400 additional contacts would develop MB disease within the following 2 years. These 11,400 contacts would otherwise have remained healthy. If this practice continued year after year, the excess of MB disease would be multiplied. Across the world, if SDR-PEP was eventually administered to 20 million people in one year, about 23,000 additional contacts would develop MB disease within the following 2 years. These contacts would otherwise have remained healthy. If the use of SDR-PEP for 20 million contacts continued year after year, then within a period of about 12 years over 230,000 additional contacts will have developed MB disease. These 230,000 contacts would otherwise have remained healthy.
It could be even worse than that. Since the MALTALEP follow-up lasted only 2 years, and the observed excess of MB cases was greater in year 2 than in year 1, an even greater excess might occur in years 3 and beyond.
Therefore, not only is SDR-PEP likely to harm the unfortunate individuals who receive it, but also it could damage our prospects of controlling HD. Increasing MB disease and selecting drug-resistant bacilli is not the way to end HD.
It is better for us to respect our duty of care to the people of endemic countries, and spare them from SDR-PEP. We need not offer a poisoned chalice to thirsty people. We are compassionate people dedicated to ending HD. Let us act accordingly, take heed of this unexpected evidence, and cease to promote or use SDR-PEP in endemic countries.
Mahatma Gandhi faced difficult predicaments. He used largely innovative and non-traditional venues and methods, constantly speaking the truth, to help set his compatriots free. So too can we speak out, in innovative ways, to ensure that people are safeguarded and SDR-PEP is no longer promoted or used in endemic countries. Some ILEP members had already been questioning SDR-PEP. Based on the new evidence, all people of goodwill can now unite to discourage SDR-PEP. The public and local leaders can be educated, to help protect the people of endemic countries from SDR-PEP.
If the people of endemic countries were well informed, those who now receive SDR-PEP and then develop MB HD would probably claim compensation for negligence, with the assistance of public-minded civil society organisations. The WHO guidelines would not help in defending such negligence claims because those guidelines preceded the MALTALEP report 2019 (1) and are consequently out of date with regard to SDR-PEP. Nor are pre-MALTALEP assumptions about SDR valid for the purpose of making predictions. Since the people of endemic countries are generally trusting and not well informed, our duty of care to them is even greater.
What about the programmatic improvements that are said to accompany the implementation of SDR-PEP? Any such programmatic improvements are available without SDR-PEP. Instead of SDR, a balanced combination of bactericidal drugs can be used. What would that look like in practice?
An effective way to interrupt transmission
Taking into account Shandong's demonstrable success (6) and global experience since, an effective and safe protocol to interrupt transmission in hyper-endemic "hot spots" is likely to look something like the following. SDR-PEP for contacts is replaced by a combination of balanced bactericidal drugs. LML's many experts from around the world can tweak and improve this protocol.
A. Serological testing (7) of the contacts of all current and former patients and the former patients themselves. (This needs to include all known former LL patients diagnosed even decades earlier)
if serologically positive then
B. Skin smear exam to help recognise and classify LL patients
1. if high BI (4+ or greater) then
Give full MB-MDT followed by post-MDT chemoprophylaxis with 3 balanced bactericidal drugs (eg., monthly rif + moxifloxacin OR clarithromycin + minocycline) - MB MDT followed by monthly RMoxMin or RCMin
2. else if smear positive with low BI or smear negative with more than 5 lesions then
Give full MB-MDT
3. else if smear negative and 1-5 lesions then
Give full PB-MDT
4. else if smear negative and no lesions then
Give a bactericidal combination (instead of SDR-PEP eg., single dose RMoxMin or RCMin)
PLUS for ALL the above categories as well as to all serologically negative contacts,
Give MIP vaccine. (8)
Note that persons with anergy are unlikely to be missed, or under-treated, using the above protocol. That is crucial for success. Success depends, of course, also on the quality of training, supplies, supervision, implementation and recording/reporting.
A protocol such as the above maximises our chances of matching or even exceeding Shandong's demonstrated 20%/year decline in incidence rate, ending in near-zero transmission.(6) Esteemed colleagues can improve this example protocol. Something along these lines seems beneficial and worthy of support from all concerned.
The Figure. The central challenge of interrupting HD transmission is to ensure that one patient with anergy does not infect another such person with anergy. The "reproductive ratio" of LL patients needs to be reduced to less than one. Shandong achieved this by ensuring prolonged anti-microbial protection for LL patients, leading to a 20% per year decline in incidence rate ending in near-zero transmission.(6) MB patients are of far greater epidemiological and clinical consequence than PB patients. Merely focusing on non-infectious and largely self-limiting PB disease will not suffice. Given the MALTALEP findings showing an excess of MB cases in the SDR-PEP group (1), SDR-PEP emerges as a threat to HD control.
Premature cessation of recruitment in the MALTALEP trial
The MALTALEP RCT protocol (5) stated that 10,000 contacts would be recruited in each group and the outcome would be clinical disease detected among contacts within the first 2 years. However, the SDR-PEP treated group showed an excess of MB cases as early as year 1 of follow-up, and this relative excess was even more marked in year 2. Therefore, quite apart from budgetary concerns, it was eminently ethical to stop recruitment prematurely, instead of exposing several thousand more contacts to SDR-PEP. Now, we too can stop exposure of people to SDR-PEP. Ethically, it seems only right.
Other matters
I merely shone a spotlight on a crucial part of the MALTALEP report 2019. (1) However, the fact stands on its own without any spotlight at all. Therefore, where the spotlight came from, or even whether there is a spotlight at all, is irrelevant.
The reliability and validity of claims and hypotheses depends on the amount of scrutiny to which they are subjected. Hundreds of knowledgeable experts, as in LML, are far more likely than 2 or 3 reviewers, or relatively small committees, to spot and correct errors. The half-life of errors is inversely proportional to the number of competent persons scrutinising. That is why modern methods of scientific communication, such as LML, have found a useful place alongside traditional journals and committees. For example, the traditional journals and committees held for over a decade that a decline in incidence rate greater than 5%/year was impossible with anti-microbial chemotherapy. Once the evidence of Shandong's success was analysed on LML, that error was corrected within a few months. Similarly, the myth of low recurrence rates after fixed duration MDT survived in the traditional journals and committees for decades. Once the relevant long-term follow-up paper was more carefully analysed on LML, that dangerous myth too was corrected within months. Flat-earthist views cannot survive for long in modern channels of rapid open scientific communication, such as LML.
Esteemed colleagues here are often high-powered professionals who are capable of forming their own view on the validity of each LML contribution. Modern scientific platforms such as LML are not only here to stay, but also they are pioneers in our transition to rapid scientific publishing with wider expert scrutiny than is customary or possible under the traditional models.
Traditional journals and modern scientific channels such as LML have complementary roles. Original research published in traditional journals provides pieces of a complex jigsaw. Accumulating such pieces is indispensable, as is accumulating clues directly from the front-lines. However, all these fragments still need constantly to be assembled into an overview, and transformed into actionable steps. LML is where that often happens, to a fairly high standard. The quality of analysis here is probably as strong as anywhere else. Contributors here are free to make it even stronger than anywhere else, to the best of their ability. Analyses here are scrutinised by a large and well-informed community, including nearly all of the world's knowledgeable HD experts. The original pieces of the jigsaw still remain available in the traditional journals. For example, the original Shandong evidence remains available in the International Journal of Leprosy. (6)
"How can you get the best ideas and have the ideas, and not the hierarchies, win?" asked Dr. Vas Narasimhan in an interview. That visionary and great friend of people with HD would appreciate the non-hierarchical nature of LML. Important insights in HD can no longer be swept under the carpet, thanks to LML.
Finally, as an aside, we can recall the story of the emperor who was given invisible garments. He went out into the streets. A little boy remarked that the emperor was naked. The question is whether the remark was true or false, not whether it was made in the street or the palace. The truth matters wherever it is uttered. In any case, for the avoidance of doubt, the excess of MB clinical disease in the SDR-PEP group is displayed in the MALTALEP 2019 report itself.(1)
Conclusion
The finding of excess MB cases in the SDR-PEP group of the MALTALEP report 2019 (1) is a fact that cannot be wished away. That aggravates the previously known risk of selecting drug-resistant HD bacilli with monotherapy (SDR). However, there are clear ways forward, as illustrated by the example protocol above. I am glad that Mr. Warne takes every part of the MALTALEP report seriously.
I have great personal regard for Mr. Warne, having known him since the 1980s. I invite him to join us all in ethically focusing on what actually works and is not harmful. We cannot afford to condone or allow unethical conduct, lest HD work become even more marginalised. Based on the evidence from the MALTALEP report (1), and for the purpose of ending HD, it would be good to spare the people of endemic countries from SDR-PEP. Instead of selecting drug-resistant bacilli and increasing MB disease by imposing SDR-PEP on endemic countries, wouldn't it be better to end HD?
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. 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.
3. Benjak A, Avanzi C, Singh P et al. Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae. Nature Communications (2018) volume 9, Article number: 352
4. Rosa PS, D'Espindula HRS, Melo ACL et al. Emergence and transmission of drug/multidrug-resistant Mycobacterium leprae in a former leprosy colony in the Brazilian Amazon. Clinical Infectious Diseases. 1 July 2019, ciz570, https://doi.org/10.1093/cid/ciz570
5. 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.
6. 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..
7. Leturiondo AL, Noronha AB, Oliveira do Nascimento MO et al. Performance of serological tests PGL1 and NDO-LID in the diagnosis of leprosy in a reference Center in Brazil. BMC Infectious Diseases volume 19, Article number: 22 (2019)
8. Sharma P, Mukherjee R, Talwar GP et al. Immunoprophylactic effects of the anti-leprosy Mw vaccine in household contacts of leprosy patients: clinical field trials with a follow up of 8-10 years. Lepr Rev. 2005 Jun;76(2):127-43.
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