Leprosy Mailing List – July 20, 2018
Ref.: (LML) Single-dose rifampicin chemoprophylaxis
From: Joel Almeida, London and Mumbai
Dear Pieter,
Dr. Tiwari believes that no statistical significance was provided in his paper (LML, July 19, 2018).
This is untrue.
The 95% confidence limits his paper provided are a test of statistical significance. It is good to do such tests. Otherwise observations which are attributable purely to random effects can mistakenly be attributed to an intervention.
In this paper the upper 95% confidence limit is 2.03. That is equivalent to a greatly increased number of new cases in the SDR group vs non-SDR. 103% more cases in the SDR group, to be precise.
Does this mean, by itself, that SDR doubles the risk of leprosy developing? Of course not. It means merely that the claim of reduced incidence in the SDR group is not substantiated by the observations in this study. It is scientifically incorrect to claim even a 0.1% reduction owing to SDR on the basis of these specific observations. Claiming a 50% reduction is even more unjustifiable.
(Incidentally, an odds ratio of 0.57 would NEVER amount to a 50% reduction, even if the confidence limits were sufficiently narrow. Science won't allow that, but hype or mere carelessness may do so.)
Leprosy is a neglected disease. That is due largely to departure from normal scientific standards, opening the door to counter-productive hype, propaganda and sub-standard treatment. Who has been paying the price for the departures from normal scientific standards? People at risk of leprosy and disfigurement due to leprosy.
I wish Dr. Tiwari and associates well in the worthwhile and very important project of trying to eliminate leprosy from a small island. But I also have good wishes for the vulnerable people who have been paying the price for departures from normal scientific standards.
Having looked in reasonable detail at the COLEP study paper mentioned, I agree with those authors that SDR (single dose rifampicin) is not chemoprophylaxis at all. Rather, it is treatment with a single dose, on the reasonable presumption that contacts will have been infected before the dose. Perhaps it can be re-labelled extremely short monotherapy (ESM) for sub-clinical leprosy.
Wouldn't it be wonderful if extremely short monotherapy turned out to be sufficient to cure sub-clinical leprosy among contacts of untreated patients, without exerting any selective pressure on the bacterial populations? It's always good to hope.
What did the COLEP study set out to examine? And what did it actually find?
It compared a single dose of rifampicin (SDR) with placebo given to contacts in the second month of starting the index patient's treatment, with follow-up for four years. Presence or absence of clinical leprosy was the observation of interest. The statistical power calculations were based on the total follow-up period of four years. All admirably good practice so far.
What did they find at the pre-defined end point of four years? A reduction of between 10% and 53% in the incidence rate of leprosy in the SDR vs placebo groups.
So, we can be reasonably certain of one thing. If you take SDR after being in contact with an untreated person who has leprosy, your risk of developing leprosy will very likely be reduced by at least 10%. Not a lot, but possibly more useful than zero efficacy.
Those authors state, very fairly, "After four years' follow-up we cannot yet establish to what extent there is a true prevention of new cases of leprosy by intervention with rifampicin. There may be merely a delay in the occurrence of disease."
There is good reason for their hypothesis of delay. They reported that more leprosy cases occurred in the SDR group than the placebo group after the first two years. That difference was not statistically significant (else we could claim, in keeping with Dr. Tiwari's preference, that SDR definitely increases the risk of clinical leprosy appearing two years or more after SDR).
Those authors, again very fairly, cite a study in Indonesia, stating "That study found no effect of rifampicin in communities where only household contacts and direct neighbours" were included.
So, in the matter of SDR, there seems to be somewhat of a gap between the facts and the hype.
Until we greatly expand the financial cake available for leprosy work, it probably makes sense to focus efforts and resources on clearly effective interventions. Rain dances might not bring rain, but they tend to be harmless as long as they remain a side amusement. Only when they preoccupy many people, as happened with the campaign to eliminate leprosy services, do they become seriously harmful.
It would be good to respect normal scientific standards in leprosy research, just as in other research. It gets us further and is less cruel to people at risk of leprosy.
I must close by emphasizing how worthwhile it seems actually to test the possibility that existing knowledge and tools can succeed in eliminating leprosy from a small island. Not just SDR alone but joined with BCG and every other trick that might half work. Either we will succeed, or we will learn why not. But our rain dance will be confined and therefore less likely to cause widespread harm.
More respect for scientific standards, fewer exaggerated claims, seems a promising way forward. My best personal wishes to Dr. Tiwari, who I hope will increasingly see the merit in normal scientific standards.
Joel Almeida
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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