Lepr Rev (2003) 74, 2±6

Editorial

UNIFORM MDT (U-MDT) REGIMEN FOR ALL

LEPROSY PATIENTS Ð ANOTHER EXAMPLE OF
WISHFUL THINKING

At the third meeting of the WHO Technical Advisory Group on Elimination of Leprosy
(TAG), key challenges to ensuring integration and sustainability of leprosy services were
identi®ed as `to further simplify and shorten the current multidrug therapy (MDT) regimens'
and `to abolish classi®cation for treatment purposes'.1 The most important and most
controversial recommendations by the group were the `large scale implementation of
accompanied MDT (AMDT)' and the `implementation of the 6-month MB MDT regimen
for all leprosy patients.'1 Later, the recommendation of a uniform MDT (U-MDT) regimen,
based on the standard MDT regimen for MB leprosy,2,3 but with a duration of treatment of
only 6 months for all types of leprosy, was endorsed, and a research protocol was approved by
the TAG at its fourth meeting.4 Because an Editorial5 calling attention to the ¯aws of AMDT
has recently been published in Leprosy Review, this paper focuses on scienti®c merits of the
recommendation of a U-MDT regimen and its research protocol.

Progress from dapsone monotherapy for all types of leprosy to different MDT
regimens for paucibacillary (PB) and multibacillary (MB) leprosy

The clinical, bacteriological, histopathological and immunological manifestations of leprosy

form a continuous spectrum.6 Thus, classi®cation has been an important subject in leprosy
research and control. The host±parasite relationship differs greatly between the two poles of
the leprosy spectrum, and their bacterial populations are different both quantitatively and
qualitatively. A heavily infected lepromatous patient may harbour as many as 1011
Mycobacterium leprae,7 and it has been observed that skin biopsy specimens from advanced
lepromatous patients contained, on average, 106 M. leprae per mg of tissue.8 Such a large
bacterial population probably includes spontaneously occurring drug resistant M. leprae.9 By
contrast, a typical tuberculoid patient is skin smear negative; the size of the bacterial
population is estimated to be no greater than 106,2 and is unlikely to include a spontaneously
occurring drug resistant bacillus.9 Consequently, the requirements for chemotherapy,
especially in terms of the number of drugs and the duration of treatment, differ between
these groups. The observations that the disease tended to relapse in skin smear positive cases
if dapsone monotherapy was discontinued,10 and that secondary dapsone resistance emerged
almost exclusively in skin smear positive patients,9 illustrate the different requirements of
smear-positive and smear-negative patients.
2 0305-7518/03/064053+07 q Lepra
 Uniform MDT for all leprosy patients 3

It is true that, during the era of dapsone monotherapy, all leprosy patients were treated
with the same regimen. However, this does not mean that a uniform regimen was desirable;
simply, that during that era, no other effective drug was available to supplement dapsone.
When a WHO Study Group met in 1981 to discuss the chemotherapy of leprosy for control
programmes,2 two major developments were taken into consideration. First, dapsone
resistance, both secondary and primary, had become a widespread phenomenon, seriously
jeopardizing the whole strategy and threatening the prospect of leprosy control. Second, a
small number of bactericidal drugs became available for the treatment of leprosy, of which
rifampicin was the most potent drug against M. leprae. Consequently, the most important
recommendation made by the Study Group was to treat all leprosy patients with rifampicin-
based MDT.2 In view of the different requirements of chemotherapy among leprosy patients,
the Study Group classi®ed leprosy into MB and PB cases according to the degree of skin
smear positivity. This was essentially an operational classi®cation to serve as a basis for
chemotherapy, because the compositions and the durations of the MDT for MB and PB
leprosy differed substantially.2

Over-treatment of PB leprosy by a U-MDT regimen

Since the concept of PB leprosy was introduced,2 its de®nition has changed several times.
Orginally, PB leprosy included indeterminate (I), polar tuberculoid (TT) and borderline
tuberculoid (BT) leprosy in the Ridley±Jopling classi®cation, or patients with an initial
bacteriological index (BI) of < 2 by the Ridley scale at all sites.2 Later, the WHO Expert
Committee on Leprosy at its sixth meeting recommended that only patients who are initially
skin smear negative should be classi®ed as PB.11 Subsequently, at its seventh meeting, the
WHO Expert Committee on Leprosy recommended that PB classi®cation should be applied
to those newly diagnosed patients who have no more than ®ve skin lesions.3 The range of
cases classi®ed as PB leprosy has progressively narrowed over the last 20 years; only about
50% of newly detected leprosy patients are now classi®ed as PB, signi®cantly less than in the
past. Employing the current de®nition,3 it is reasonable to suspect that PB patients may
respond to chemotherapy more homogeneously, and probably with some self-healing.
Despite changes in the de®nition of PB leprosy, the composition and duration of the
standard MDT regimen for PB leprosy remains unchanged. Several million PB patients have
now completed their treatment; the great majority of them, classi®ed by whichever de®nition,
responded very well to the two-drug regimen administered for 6 months, and there is no major
disagreement regarding the low PB relapse rate after MDT. One could therefore consider the
possibility of shortening the duration of MDT for PB leprosy to less than 6 months. Although,
in theory, monotherapy with rifampicin should be suf®cient for the treatment of PB leprosy,2
in order to minimize the risk of emergence of rifampicin resistance among MB patients who
have been wrongly classi®ed as PB leprosy, it is safer to continue to use the two-drug
combination.
However, the recommendation of a U-MDT regimen for all leprosy patients points to the
opposite direction. Instead of shortening the duration of MDT for PB leprosy, the TAG has
recommended treatment of PB leprosy with three drugs, daily dapsone and clofazimine plus
monthly rifampicin and a supplementary larger dose of clofazimine, for 6 months. The
recommendation to add clofazimine to the current MDT regimen for PB leprosy lacks any
scienti®c indication or justi®cation, and PB patients will be over-treated by the U-MDT
4 B. Ji & P. Saunderson

regimen. Furthermore, because clofazimine is a relatively expensive drug and may cause
side-effects,2 implementing the U-MDT regimen would increase the cost of treating PB
leprosy, and unethically expose patients to an additional risk of side-effects.

Premature attempt to shorten the duration of MDT for MB leprosy to 6 months

The ¯aws in recommending the U-MDT regimen for the treatment of MB leprosy are quite
different: instead of over-treatment, MB patients might be under-treated by the U-MDT
regimen. According to the TAG, the rationale for recommending a U-MDT regimen was that:
`MDT has been shown to be robust in terms of treatment ef®cacy and safety. Relapse rates are
very low (less than 1%), resistance to MDT is virtually non-existent, and relapse cases can
still be cured by MDT.'1 How true is this statement?
First, a regimen is de®ned both by its composition and its duration. Although the
composition of the MDT regimen for MB leprosy has remained unchanged, the duration
of treatment has been progressively shortened, from `at least two years and be continued,
whenever possible, up to smear negativity',2 to 24 months,12 and then to 12 months.3 With
respect to ef®cacy, although there are data on long-term relapse rate after treatment with
24-month MDT, but there are none after 12-month MDT, which has been the regimen of
choice for MB leprosy since 1998. Until this information becomes available, no conclusion
can be reached regarding the long-term ef®cacy of 12-month MDT, and there can be no
justi®cation for further shortening the duration of MDT for MB leprosy to 6 months.
Secondly, there is disagreement on the magnitude of MB relapse after 24-month MDT
and the possible existence of a higher-risk subgroup of MB patients who are more prone to
relapse.13,14 TAG has completely ignored the observations of high relapse rates, as high as
4±7 per 100 patient years among patients with initial BI of 5 4´0, reported by some research
institutes.15,16
Thirdly, the conclusion that resistance to MDT is virtually non-existent1 or completely
absent4 cannot be supported by evidence, because post-MDT surveillance for relapse was
discontinued since 1994,12 and susceptibility to rifampicin has rarely been tested since the
introduction of MDT.17 The history of leprosy has repeatedly demonstrated that a phenomenon
may exist despite not being reported; the problems of poor-adherence18 to self-administered
dapsone, and frequency of relapse caused by dapsone resistance9 were thought to be negligible,
but became apparent only after serious studies were conducted. It would be more reasonable to
conclude that, at present, the frequency of rifampicin resistant leprosy is unknown.

Flaws in the research protocol `Uniform MDT regimen for all leprosy patients'

According to the protocol, the project requires 5000 newly detected, previously untreated
leprosy patients, 2500 MB and 2500 PB; patients will be examined clinically for evidence of
relapse for 5 years after completion of treatment; and the maximum acceptable cumulative
relapse rate has been predetermined at 5% at the end of 5 years.4
The major ¯aws in the protocol are the following:
· There is no reason to include PB patients in a trial to determine relapse rate, because
several million PB cases have already been successfully treated with 6-month standard
MDT; thus half of the resources for the trial are being wasted.
 Uniform MDT for all leprosy patients 5

· In the current protocol, there is no control group in which MB patients are treated with the
standard 12- or 24-month MDT regimen. As a consequence, it will not be possible to
compare the ef®cacy of the U-MDT regimen for MB leprosy with that of the standard MDT
regimen.
· The de®nition of MB leprosy, i.e. all patients with more than ®ve skin patches,4 is too
broad, and will include many cases who are indeed PB leprosy from the bacteriological and
chemotherapeutic points of view.2 As a research project, the tested subjects should be as
homogeneous as possible, and therefore the study should focus only on skin smear positive
patients.
· The de®nition of relapse, i.e. the ®nding of one or more new skin patches consistent
with leprosy,4 is too vague; based on this de®nition, a health worker would have
dif®culty in distinguishing relapse from leprosy reaction. More important, because skin
smear examination, one of the key indicators for diagnosing MB relapse,15,19,20 is not to
be employed, the sensitivity and speci®city of diagnosing MB relapse will be seriously
compromised.
· The average incubation period of MB relapse after treatment with rifampicin-containing
regimens is over 5 years.15,19,21 In order to detect the majority of MB relapses, patients
should be followed for more than 5 years after stopping treatment, otherwise only a
proportion of the relapses will be detected,15,21 leading to an over-estimation of the ef®cacy
of the tested regimen.
· In routine programmes, the cumulative relapse rate for PB or MB leprosy is around 1% at 9
years after completion of standard MDT;3 there is no justi®cation for accepting a
predetermined cumulative relapse rate of 5% at the end of 5 years of the trial.4
· The relapse rates for PB and MB casesÐor more ideally, for smear-negative and smear-
positive casesÐshould be calculated separately. A pooled relapse rate of all patients may
mask an unacceptably high relapse rate amongst smear-positive individuals. For example,
a 5% relapse rate would give 250 relapses in the study population of 5000; if there are only
200±400 cases with an initial BI of 5 4, a relapse rate of over 50% in this high initial BI
subgroup would be needed before the U-MDT regimen was declared ineffective by the
proposed criterion.

Conclusion

It is wishful thinking to ignore the fact that the requirements for chemotherapy are different
among various subgroups of leprosy patients, and to recommend a uniform regimen for all
leprosy patients. A U-MDT regimen would over-treat PB leprosy, waste substantial amounts
of resources, and unethically expose patients to the risk of side-effects caused by clofazimine.
Moreover, none of the reasons for treating MB leprosy with U-MDT regimen is valid. If one
cannot exclude the possibility that MB patients, particularly those with a high initial BI, may
be under-treated by U-MDT, there would be serious ethical problems in recommending the
regimen. Substantial modi®cations are needed to address the ¯aws in the research protocol,
otherwise it is likely that the trial will not reach a clear-cut conclusion; or even more
seriously, that the study will produce an invalid conclusion in relation to the small subgroup
of patients with high initial BI.
The website www.clinicalevidence.com contains a review of all the published literature
on chemotherapy trials in leprosy.22
6 B. Ji & P. Saunderson

BacteÂriologie et HygieÁne BAOHONG JI

Faculte de MeÂdecine PitieÂ-SalpeÃtrieÁre
91, boulevard de l'HoÃpital
75634 Paris, France
(e-mail: [email protected])
American Leprosy Missions, PAUL SAUNDERSON
Greenville, SC, USA

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