Leprosy Mailing List – December 22, 2018
Ref.: (LML) New WHO guidelines on chemotherapy for PB leprosy
From: Ruth Butlin, Nilphamari, Bangladesh
Dear Sir,
Many readers of leprosy mailing list will be aware that WHO recently produced new Guidance on Diagnosis, Treatment and Prevention of leprosy. (available from www.searo/who.int/entity/global_leprosy_programme/en/ ).
This includes a recommendation to make triple therapy (for 6 months) the standard regimen for all PB cases.
We do appreciate the effort taken by the Guidance Development Group (GDG) to review literature and extract evidence, however it appears to us that the conclusions reached do not accurately reflect the findings. Any unsafe recommendations from an august body such as the WHO will carry a high risk; because advice from the WHO is generally highly regarded, the recommendations may be uncritically & precipitately accepted into daily practice.
The recommendations are primarily addressed to clinicians and programme /policy makers. Many clinicians in the field of leprosy are not really free to make individual decisions as they are constrained by Official Guidelines, while working under a National Leprosy Elimination Programme (government staff or NGO staff who are providing services on behalf of the Ministry of Health in a certain area). However, those who bear clinical responsibility should be prepared to justify (to patients, colleagues or managers) their therapeutic decisions, as far as possible by reference to published evidence. Some programme managers who do not themselves have clinical responsibility, may be responsible for a variety of disease control programmes and so not able to keep themselves fully up to date with developments in relation to each disease. They would be wise to take heed of feedback from clinicians familiar with the latest evidence on best practices.
If anyone has seen only the Executive Summary (published earlier), I would strongly recommend also reading carefully the full document to understand the reasoning of the GDG. This is a well-constructed document laying out the decision-making process which preceded the publication of new guidance. For those who wish to further study the evidence base, another pdf entitled "Literature Review" is available from the same website.
The GDG itself says the evidence is weak for its new recommendation on chemotherapy for PB cases ( part 2,section 2.1):
"The GDG recommends the same 3-drug regimen with rifampicin, dapsone and clofazimine for all leprosy patients, with a duration of treatment of 6 months for PB leprosy and of 12 months for MB leprosy (conditional recommendation, very low-quality evidence)".
Note that the recommendation is said to be CONDITIONAL (implying it is not a final decision, not immutable, may change when new evidence is forthcoming. The GDG recognises the need for more information ….. until such time as conclusive evidence is available, it seems to us there is no justification to change from what is current standard therapy, which is satisfactory for the majority of PB cases (unfortunately not for those susceptible to dapsone hypersensitivity syndrome).
It would be wise for programme managers to use their discretion and not rush into changes of policy purely on the basis of this new WHO publication, but rather to wait for both an independent expert assessment of the recommendation, by people with skills to critically appraise evidence, and for considered responses from those with field experience as to what the implications might be. Some more comments from affected people (with PB leprosy) in a wider variety of countries would be valuable, including from people who received clofazimine for PB leprosy eg because of dapsone intolerance.
Our immediate concerns are as follows
1. How will this change affect children? A high proportion of children with leprosy have the PB type. In some leprosy-endemic countries where malnutrition as well as enteric infestations and infections common, will many of the young children have adverse effects such as diarrhoea due to the clofazimine component of MDT? This might exacerbate malnutrition and also impair absorption of dapsone and rifampicin. Anorexia/nausea due to clofazimine may lead to refusal by the child patient of other prescribed drugs including dapsone & rifampicin. Some of these young children are of very low body weight, will the doses be appropriately adjusted by peripheral health workers dispensing MDT? The authors' personal experience is that in some clinics standard "child packs" are issued (unmodified) to children of all sizes, including those under 30kgs body weight. Since the smallest available capsule of clofazimine contains 50mg, it is difficult to accurately adjust the dosage for very small children (under 15-20kg). Accumulation of clofazimine in a child's body means it could take a long time for adverse effects to subside, even after stopping intake.
2. How will this change affect compliance? The combination of extra pill burden, gastro-intestinal side effects and pigmentation may discourage people from continuing consumption of MDT. When clofazimine is given to PB cases the increase in pigmentation, concentrated in patches (especially if they are on sun-exposed areas of the body), may be more conspicuous than the evenly distributed hyperpigmentation seen with diffuse infiltration in LL cases, causing social embarrassment.
3. How will this change affect Health Workers' practices? It would be worrying if Health Workers began taking over-seriously the GDG's comment (p. 18) that misclassifying leprosy cases (calling MB cases PB) will be less of a problem with the new regimen (since all have the same 3 drugs), since the recommended duration of chemotherapy is still different. The GDG clearly states (p.19) that they are unable to recommend only 6months of triple therapy for MB cases, as there is not enough evidence of its efficacy. Correctly allocating cases to MB or PB leprosy groups is as important as ever. The most serious errors can be avoided by use of skin smears.
4. How far is this proposed change driven by considerations of cost? The GDG predicts that for global leprosy control it will be cheaper overall to manufacture and distribute only two type of lister calendar packs (one for adults and one for children, each with three drugs). The extra cost of the clofazimine component would, nevertheless, be significant in situation where people purchase their own MDT (organisations, or individuals being treated in the private sector). However, cost should only be a deciding factor in choice of regimens where the alternatives are proven to be equally safe and effective and acceptable.
This brings us back to the question: WHO asked the GDG to consider the complex question (part 1, section 6.2) "Is a single (uniform) treatment regimen (ie of three drugs for 6months) for all patients with leprosy as effective and safe as the currently recommended treatment regimens: the one for MB leprosy with a combination of three drugs for 12 months and the one for PB leprosy with a combination of two drugs for 6 months? ", but the really important question ( for PB cases) is not "whether three drugs is as good as two", but rather "is the three drug therapy more effective, or safer, than the two drug therapy?" Only if the latter question can be unequivocably answered with "yes", can we be justified in abandoning the established practice of using, as first choice for the majority of PB cases, the familiar two drug chemotherapy regimen for 6 months.
So, the challenge to LML readers is two-fold:
Firstly, do we accept these "conditional recommendations" and implement them immediately?
And secondly: can we produce more good quality, relevant, evidence to inform our decisions? Please see, at the end of the WHO document, an appeal (part 3, section 2): "Adequately powered, appropriately designed studies are needed on the benefits and harms of shorter MDT regimens for MB leprosy, including effects on bacteriological outcomes …... For both PB and MB leprosy, more well conducted studies are needed to better understand optimal treatment strategies".
If everyone blindly follows the new suggestion to use triple therapy routinely for PB cases, there will never be adequate information to prove whether this over-treatment has caused more adverse effects and no greater benefit
Yours faithfully,
C Ruth Butlin (Medical advisor to Rural Health Programme, The Leprosy Mission Bangladesh)
Benjamin Jewel Rozario (Resident Medical Officer, DBLM hospital, Nilphamari, Bangladesh)
LML - S Deepak, B Naafs, S Noto and P Schreuder
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