E-DRUG: BMJ on leprosy treatment
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[BMJ editorial on leprosy treatment; thanks to Valeria for spotting; copied as fair use. WB]
BMJ 2004;328:1447-1448 (19 June),
Editorial
Treatment of leprosy: The evidence base for newer drug combinations and shorter regimens is weak
Leprosy still poses major therapeutic challenges. We have effective antibiotics to cure the infection, but the immune mediated peripheral nerve damage can continue long after effective antimicrobial treatment has started, and patients continue to be stigmatised. Effective management should therefore include treatment of nerve damage and reactions, prevention of disability, and reduction of stigma. The regimens recommended by the World Health Organization of six or 24 months' multidrug treatment (rifampicin, dapsone, and clofazimine) produce good clinical responses and low rates of relapse. The long-term outcome for shorter regimens and other drug combinations, however, is not known. Testing for recent nerve damage and treating it with steroids is essential. Dermatologists already have an important role in treating patients in the large Indian and Brazilian cities, and this is likely to increase as leprosy programmes are integrated into primary care.
Antimicrobial chemotherapy
The WHO recommended multidrug regimen of rifampicin,
clofazimine, and dapsone has been used since 1982. It is highly
effective, and more than 11.2 million patients have received it.1 2
Patients receive rifampicin 600 mg monthly, dapsone 100 mg
daily, with clofazimine 300 mg monthly and 50 mg daily added in
for patients with multibacillary leprosy. The clinical classification
uses the number of skin lesions for grouping patients into
paucibacillary (five or fewer lesions) and multibacillary (more than
five lesions) leprosy.3 Where possible, slit skin smears should be
done and patients with detectable bacilli should be treated with the
multibacillary regimen. The initial recommendation was that
patients with paucibacillary leprosy should be treated for six
months and those with multibacillary leprosy for 24 months.1 A
recent paper in Clinical Evidence has collated data from
observational studies and shows the value of complying with
these simple, WHO recommended regimens.4 Monthly
supervision of treatment has also been critical to success.
One of the subtleties of treating leprosy is the lack of clear cut end
points of treatment. Up to 42% of patients with paucibacillary
leprosy may still have active skin lesions at the end of treatment
because of the continuing immune responses, but this does not
denote failure of treatment.4 Relapse rates are impressively low
for paucibacillary and multibacillary regimens, ranging from 0% in
China to 2.04 per 100 person years in India.4 These regimens
confirm the effectiveness of a single monthly dose of rifampicin
and avoid the toxicity experienced with daily rifampicin. In 1998 the
WHO technical advisory group noted that multibacillary patients
could probably be treated with only 12 months of multidrug
therapy.1 However, no long term relapse data are currently
available for this regimen, and many healthcare providers prefer to
continue with the evidence based 24 month regimen.
Studies from India and Mali show that patients with a very high
initial bacterial load (bacterial index more than 4+ on skin smear)
have higher relapse rates (four to seven per 100 person years)
and these relapses may occur late (averaging five years after
treatment).5 6 The Indian study compared relapse rates in
patients with a very high initial bacterial load either given 24
months' treatment or until slit skin smears were negative; the
relapse rate was much higher in the group treated for 24 months,
and this only emerged after four years of follow up after treatment.5
One option is to give such patients the choice of being treated until
their skin smears are negative or being kept under regular review.
The place of the drug combination rifampicin, ofloxacin, and
minocycline is also unclear. It was used as a single dose for
single skin lesions but in a large study from India was found to be
less efficacious than the standard paucibacillary-multiple drug
therapy (PBMDT) regimen, given for six months.7 Monthly
rifampicin, ofloxacin, and minocycline in combination has been
used in both multibacillary and paucibacillary disease, with good
clinical responses.8 Although the initial response to this new
regimen may be good, the critical question is the relapse rate over
the following 10 years, and this requires careful long term studies
before the regimen can be recommended generally. At this point it
would be unwise to abandon the well proved WHO regimens.
Nerve damage
Detecting and treating nerve damage early is the key to preventing
deformity. Nerve damage may occur before diagnosis, during
treatment, or after it. Thirty per cent of patients with multibacillary
leprosy will either have a reaction or develop new nerve damage,
often within the first few months of starting anti-leprosy drugs.
Assessing and monitoring peripheral nerve function should be
part of the routine assessment of every patient. Data from
Bangladesh show that the patients at highest risk of developing
new nerve impairment were those with multibacillary leprosy, with
pre-existing impairment, who had a 65% risk of new damage.9
Paramedical workers in leprosy programmes have acquired
considerable skills in palpating nerves for tenderness, testing
muscle function in hands and feet, and assessing sensory loss
with monofilaments every month. Dermatologists should do this
routinely too. The nylon Semmes-Weinstein monofilaments for
detecting sensory loss were developed for use in leprosy
programmes and have recently been taken up by diabetes
programmes. Patients presenting with new muscle weakness or
sensory loss should be treated with a course of prednisolone,
starting at 30-40 mg daily.10 Preventing new nerve damage
remains a challenge, as illustrated by the double blind
randomised controlled trial reported in this issue of the BMJ11 (p
1459). New multibacillary patients were randomised to receive
either 20 mg of prednisolone or placebo for the first four months of
treatment. Whilst new nerve damage was reduced during steroid
treatment, when steroids were stopped there was an increase in
nerve damage. This suggests that the biological mechanism of
nerve damage is a powerful long lasting immunological event.
This trial's results do not support the routine use of prophylactic
steroids in all multibacillary leprosy patients. Type 1 (reversal)
reactions affecting skin and nerve should be treated with a four to
six month course of steroids. Type 2 (erythema nodosum
leprosum) reactions affect about 20% of patients with lepromatous
leprosy. These episodes can be treated with a short course of
steroids. In severe and repeated episodes thalidomide is more
effective than steroids, but it must be used with great care,
especially in premenopausal women.12
For many patients leprosy is a devastating diagnosis, and they
need reassurance that they will be non-infectious within 72 hours
of starting treatment, cannot pass on the infection by touch, and
will not necessarily develop deformities.
The contribution that dermatologists make to the treatment of
leprosy is increasing. The integration of leprosy into mainstream
services offers opportunities for developing improved links with
dermatologists. Leprosy programmes could become more
effective by involving dermatologists in training for neurological
assessment, providing monofilaments, physiotherapy, and
footwear for patients with established nerve damage.
Diana N J Lockwood, consultant leprologist
Hospital for Tropical Diseases, London WC1E 6AU
(diana.lockwood@lshtm.ac.uk)
Bhushan Kumar, professor of dermatology
Department of Dermatology, Venereology and Leprology,
Postgraduate Institute of Medical Education and Research,
Chandigarh, India (kumarbhushan@hotmail.com)
------------------------------------------------------------------------
Papers p 1459
Competing interests: DNJL was a paid adviser to Pharmion
during their application to the European Medicines Agency to have
thalidomide licensed for use in the treatment of erythema
nodosum leprosum.
References
1. World Health Organization. Chemotherapy of leprosy for control
programmes. Geneva: WHO, 1982. (Technical Report Series,
675.)
2. World Health Organization. Report on third meeting of the WHO
technical advisory group on elimination of leprosy. Geneva: WHO,
2002. WHO/CDS/CPE/CEE/2002.29
3. WHO Expert Committee on leprosy. Seventh report. Geneva,
World Health Organization, 1998. (Technical Report Series, 874.)
4. Lockwood DN. Leprosy. Clin Evid 2002;8: 709-20.[Medline]
5. Girdhar BK, Girdhar A, Kumar A. Relapses in multibacillary
leprosy patients: effect of length of therapy. Lepr Rev 2000;71:
144-15.[ISI][Medline]
6. Ji B. Does there exist a subgroup of MB patients at greater risk
of relapse after MDT? Lepr Rev 2001;72: 3-7.[ISI][Medline]
7. Lockwood DN. Rifampicin, ofloxacin and minocycline (ROM) for
single lesions in leprosy. What is the evidence? Lepr Rev 1997;6:
299-300.
8. Villahermosa L, Fajardo T, Abalos R, Cellona R, Balagon M,
dela Cruz E, et al. Parallel assessment of 24 monthly doses of
rifampicin, ofloxacin and minocycline (ROM) versus 2 year WHO
multidrug therapy (MDT) in multibacillary leprosy. Am J Trop Med
Hyg (in press).
9. Croft RP, Nicholls PG, Steyerberg EW, Richardus JH, Withington
SG, Smith WC. A clinical prediction rule for nerve function
impairment in leprosy patients-revisited after 5 years of follow-up.
Lepr Rev 2003;74: 35-41.[ISI][Medline]
10. Britton WJ. The management of leprosy reversal reactions.
Lepr Rev 1998;69: 225-34.[ISI][Medline]
11. Smith WCS, Anderson AM, Withington SG, van Brakel WH, Croft
RP, Nicholls PG, et al. Steroid prophylaxis for prevention of nerve
function impairment in leprosy: randomised placebo controlled
trial (TRIPOD 1). BMJ 2004;328: 1459-62.
12. Lockwood DN, Bryceson ADB. The return of thalidomide: new
uses and renewed concerns-a reply. Lepr Rev 2003;74:
290-3.[ISI][Medline]
Other related articles in BMJ:
Papers
Steroid prophylaxis for prevention of nerve function impairment in
leprosy: randomised placebo controlled trial (TRIPOD 1).
W Cairns S Smith, Alison M Anderson, Stephen G Withington, Wim
H van Brakel, Richard P Croft, Peter G Nicholls, and Jan Hendrik
Richardus
BMJ 2004 328: 1459-0. [Abstract] [Abridged text] [Full text]
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