Clinics in Dermatology (2015) 33, 55–65

Treatment of leprosy
Hemanta Kumar Kar, MD ⁎, Ruchi Gupta, MD
Department of Dermatology, STD, and Leprosy, PGIMER & Dr RML Hospital, New Delhi, 110001, India

Abstract Leprosy is a curable disease, having been eliminated from many countries, including India.
This has been possible due to the wide availability of effective and safe drugs. Treatment of leprosy has
undergone considerable changes over decades, from chaulmoogra oil in 1915 to dapsone monotherapy
in 1946, then eventually to multidrug therapy (MDT) in 1982. In the last two decades, reports of
resistance to all first-line drugs have appeared in the literature, with the need to conduct clinical trials
using newer but highly bactericidal drugs and their combinations against Mycobacterium leprae.
© 2015 Elsevier Inc. All rights reserved.

Introduction First-line drugs

Leprosy plays a significant role in development of
disabilities and deformities seen in the world’s population.
Despite its elimination from a large part of the world, leprosy
remains an important health problem, especially in major
endemic countries like India and Brazil. 1 Since the
introduction of multidrug therapy (MDT) in 1982, spectac-
ular success has been achieved in reducing the disease
burden; it has helped not only in reducing the duration of
treatment but also in addressing the problems related to
resistance to antileprosy drugs, relapses, and disabilities.
MDT is not invulnerable to poor compliance (related to long
duration and other socioeconomic factors) and drug
resistance.2 There has been a renewed effort to find newer
regimens that may further shorten the duration of therapy and
improve compliance, while simultaneously maintaining or
improving the therapeutic advantages of previous regimens.
⁎ Corresponding author. Tel.: 9868506372.
E-mail address: hkkar_2000@yahoo.co.in (H.K. Kar).
The backbone of current treatment of leprosy is formed
by MDT consisting of dapsone, clofazimine, and
rifampicin. Detailed descriptions of individual drugs are
given here and their pharmacokinetics are summarized
in Table 1.
Dapsone (4,4-diaminodiphenylsulfone)
Before the introduction of dapsone as a therapeutic option
for leprosy in 1946 by Guy Faget,3 intradermal injection of
chaulmoogra or hydnocarpus oil (derived from seeds of an
herbal tree) and its esters with weak antileprotic property
were the mainstay of treatment of leprosy.4
Dapsone is a bacteriostatic drug that acts by competitive
inhibition of the enzyme—dihydrofolate synthetase and
dihydrofolate reductase, key enzymes in the folate biosynthe-
sis pathway in M leprae.5 In patients on dapsone monotherapy,
the killing of bacilli was complete in 3 to 6 months, and
complete clinical regression usually takes around 2 to 3 years.
As with all antileprosy medication, mucosal lesions are first to
heal, resulting in clearing of nasal passages, subsidence of
epistaxis, and decrease in foul smell from the nose, followed by
skin ulcers, whereas regression of nodules and skin thickening

http://dx.doi.org/10.1016/j.clindermatol.2014.07.007
0738-081X/© 2015 Elsevier Inc. All rights reserved.
56 H.K. Kar, R. Gupta

Table 1 Pharmacokinetics of various chemotherapeutic agents

Drug Absorption Metabolism T1/2 Excretion MIC Peak serum No. of days Dose
(μg/ml) level (PSL) for which (mg/kg)
achieved PSL achieved
exceed MIC
Dapsone 99%, Acetylation and 28 hr Feces 0.03 0.4-1.2 mg/ml 10 1-2 mg/kg
PSL a are N-hydroxylation (500-600 (100)
reached in in liver b times MIC)
4-6 hrs
Acedapsone PSL in 1 wk Same - Feces 0.03 8 times MIC 200 225 mg once
in 11 weeks.
Rifampicin 90%, Better in De-acetylation and 12 hr 35% in 0.3 6-8 μg/ml 1 10 mg/kg
empty stomach, oxidation in liver urine & (45-70 times (600)
PSL in 2-3 hr 65% in MIC)
feces
Clofazimine 30%-50% Kidney: one conjugated 60 days 1% in - 50 mg -0.5 - 50 mg
and two unconjugated Urine μg/ml 300mg- (daily)
metabolites. one by 1.0 μg/ml 300mg
hydrolytic dehalogenation (MSD)
& 2nd by hydrolytic
deamination followed by
glucuronidation
Clarithro- 50% Liver: 14-hydroxy 5-7 hrs Both 0.125 10 times MIC - 500mg/d
mycin Clarithromycin c is urine and (12.5 mg/kg)
almost twice as active. feces
Minocycline 95%-100%, Liver: 9- 15-23 hrs Feces 0.2 10-20 times - 100mg/d
not affected hydroxyMinocycline MIC
by meals
Ofloxacin 98%, PSL metabolized predominantly 4-5 hr Excreted - - - 500mg/d
in 1-3 hr by the liver by kidney
a
Peak serum levels.
b
Dapsone is acetylated polymorphically that is, some patients rapidly acetylate dapsone to monoacetyldapsone (MADDS) whereas in others, this process
occurs slowly; however, in all patients, MADDS is rapidly de-acerylated. Thus, equilibrium between MADDS and Dapsone is quickly reached and
sustained. Dapsone's efficacy and half life appear unrelated to the rate of acetylation. The more clinically significant metabolic pathway involves
hydroxylation of one of the amino groups by cytochrome 3A4 (and, to a lesser extent, 2C9) to form Dapsone hydroxylamine, a potent oxidant that is
important in the development of methemoglobinemia and hemolysis.
c
Adjustment of dosage is not necessary in patients with impaired renal function.

starts later. Nerve thickening, sensorimotor loss, and trophic
ulcers respond very slowly and often incompletely. The eyes
and extremities need special care and protection from trauma
and burns.5 Although well tolerated, dapsone does have some
well-known side effects (Table 2).
It was a boon to leprosy patients that was soon clouded by
emergence of dapsone resistance in 1960 (Table 3). To
overcome this threat and to improve treatment efficacy, in
1982 the World Health Organization (WHO) recommended
MDT for leprosy, consisting of concomitant use of two or three
drugs in treatment of leprosy.
Rifampicin
The morphologic index (MI) comes to zero within 4 to 6 weeks
of treatment; however, bacteriologic index (BI) takes longer to
decline. A single dose of 1500 mg or 3 to 4 daily doses of 600
mg of the drug given to patients appear to kill more than
99.99% of the viable M leprae, as tested in the mouse footpad.
Based on the earlier reports, the WHO study group
recommended 600 mg once-monthly supervised doses to
adults. Side effects (Table 2) are rare with once-a-month
dosage. Unfortunately, the exciting usefulness and benefit were
soon superseded by emergence of resistance caused by
mutation in the Rpo B gene (Table 3).
Clofazimine

Rifampicin, the only bactericidal component of MDT
against M leprae, was introduced in 1970. It acts by selective
inhibition of bacterial DNA-dependent RNA polymerase and
blocks RNA synthesis.6 The drug is also effective against
dapsone-resistant organisms. Rifampicin crosses the cell
membranes and is effective in killing intracellular organisms.
Clofazimine is a brick red, fat-soluble crystalline dye with
bacteriostatic and antiinflammatory action, whose biochemical
basis for antimicrobial actions remains to be elucidated. The
drug possibly acts by blocking the template function of DNA,
by increasing lysosomal enzyme synthesis, and by increasing
phagocytic capacity of macrophages.7 It binds preferentially to
Treatment 57

Table 2 Side effects of various first-line antileprotic drugs45

Dapsone Gastric intolerance
Hemolytic anemia (esp. in G6PD deficiency)
Methemoglobinemia
Hepatotoxicity
Peripheral neuropathy (distal motor axonopathy)
Drug eruption
Dapsone syndrome- type IV hypersensitive reaction; triad of fever, erythematous eruption,
and lymphadenopathy
Agranulocytosis (rare)
Clofazimine Reddish-brown pigmentation of skin (seen in 75%-100% patients)
Ichthyosis and dryness (seen in 8%-28% patients)
Erythroderma, acneiform eruptions, monilial cheilosis (seen in b 1% cases)
Subacute intestinal obstruction
Corneal xerosis
Bull’s eye retinopathy
Rifampicin Hepatotoxicity, thrombocytopenia, acute renal failure due to interstitial nephritis, osteomalacia.
Respiratory syndrome (dyspnea, cough and fever), flu-like syndrome (chills, shivering, fever,
headache, bone and joint pains), gastrointestinal problems—nausea,
vomiting, diarrhea, pain in abdomen

GC(guanine-cytosine)-rich region of mycobacterial (not
mammalian) DNA. Its antiinflammatory property and effec-
tiveness in treatment of type 2 leprosy reactions (T2R) is via
stimulation of prostaglandin E2 (PGE2) synthesis and
inhibition of neutrophil motility, together with selective
suppression of Th1 subtype of T helper cells.8 Interleukin 2
(IL-2) is a major cytokine in type 1 leprosy reactions (T1R),
which causes neuritis, and its production is stimulated by nuclear
factors of activated T cells (NFAT) and nuclear factor-κB
(NFκB). Clofazimine selectively blocks the Kv1.3 potassium
channel activity, perturbing the oscillation frequency of the
calcium-release activated calcium channel, which in turn leads
to the inhibition of the calcineurin-NFAT signaling pathway.9
Although slow to act, resistance to clofazimine is very
rarely reported, which possibly could be due to its multiple
mechanism of actions.10 Various adverse events encountered
with daily use are listed in Table 2. Most common and evident
is the reddish discoloration of the skin and various secretions,
the result of accumulation of large quantities of the drug in
skin, subcutaneous fat, liver, lungs, adrenals, kidneys, lymph
nodes, and gastrointestinal tract. The drug is very slowly
excreted from the body, usually taking 6 to 12 months on
average. It takes more than 3 years for patients to regain their
normal coloration after stoppage of clofazimine. This
accumulation of clofazimine in the macrophages possibly
interferes with the capacity of macrophages to process and
present antigens, thereby preventing their mobilization and
activation, IL-2 release, and clonal expansion. Clofazimine is
active against dapsone-resistant M leprae. The drug should not
be used alone, nor is it a replacement for the cheaper and more
effective drug, dapsone.
Multidrug therapy
Introduction of MDT in 1982 was the most prodigious step
taken by the WHO Expert Committee in the history of leprosy.
It rapidly became the standard treatment of leprosy and has

Table 3 Resistance to various drugs used in treatment of leprosy45

Drug Gene Enzyme Remarks
Dapsone Mutation in codon 55 of Dihydropteroate Frequency among leprosy patients: 1: 250 to 1:1000
folP gene (substitution of
synthase (DHPS) Because resistance to Dapsone is a multi-step phenomenon.
leucine for proline) Therefore, all grades or degrees of resistance are encountered
Risk of relapse due to resistance is around 2%-3%,
Clinical appearance of relapse, d/t secondary Dapsone resistance,
takes around 5-15 yrs
Rifampicin rpoB gene (codon 531: RNA polymerase Probability is lower- 1 in 109
TCG to TTC). Results in reduced penetration of Rifampicin into bacterial cells
Flouroquinolones single step mutation DNA gyrase Probability is still lower (less than 1 in 109 organisms).
in gene gyrA Leads to decrease in penetration of drug in bacterial cells
Clarithromycin plasmid mediated, erm gene ribosome Cross-resistance with clindamycin and lincosamides
methylases
58 H.K. Kar, R. Gupta

Completion of 12 months
been supplied by WHO free of charge to all endemic countries

9 consecutive months
18 consecutive months
since 1995. The concept of giving multiple drugs for treatment
from treatment (RFT)

6 monthly pulse in
of leprosy was based on an estimation that an advanced,
Criteria for release

pulses course in
untreated lepromatous leprosy patient harbors about 11 logs

Completion of
live organisms. Out of these, the proportion of naturally
occurring drug-resistant mutants is estimated to be 1 in 7 logs
for rifampicin; 1 in 6 logs each for dapsone and clofazimine.
The organisms resistant to one drug will be susceptible to the
other drugs in MDT, because their mechanisms of action are

(weekly twice)
——————

——————

alternate day
Dosage Below

different. With combination therapy, the probability of

25 mg daily
or 50 mg
emergence of mutant resistance to any two drugs reduces to
10 years*

1 in 13 logs, which is negligible.11 The regimen is tabulated

100 mg

300 mg
300mg

25 mg
50 mg

in Table 4.
Since its introduction, MDT has not undergone much
———————

revision except for the duration of therapy. Initially, the

——————
Dosage children

alternate day)

duration of treatment with MDT was very long (eg, 24 months

50 mg (every

or until smear negativity), which was responsible for decrease

10-14 yrs

in compliance, resistance, and relapse. Based on observation of

450 mg

150 mg

450 mg
50 mg

50 mg

the Bombay Leprosy Project and WHO12 on fixed-duration

treatment (FDT) for 6 and 12 months (FDT-12/6) for
multibacillary (MB) and paucibacillary (PB) groups, respec-
———————————

——————————

——————————

tively, the number of relapses was found to be insignificant

compared with the cost of FDT for 24 months; hence, in 1997,
FDT-12/6 for MB/PB was introduced worldwide. The
advantages of short-duration therapy are reduction in the
Dosage adult/
above 15 yrs

number and degree of deformities in new cases due to

increased self-reporting of patients at an early stage of their
600 mg

300 mg

100 mg

600 mg
100 mg
50 mg

disease as a result of improved control programs and publicity

about the new short-term therapy, which in turn leads to
increased acceptance and compliance of patients with
—————————————

treatment and, finally, better community support of patients.

————————————

To simplify the treatment schedule for patients, WHO in

——————————

collaboration with Novartis Pharma (Switzerland) supply

MDT in “blister packs” (Figure 1). Each blister pack contains
treatment for 4 weeks. The patient is asked to visit the
(every other day

leprosy center monthly to collect the monthly blister pack

Daily for adult
administration
Adult(children

for children)
Once monthly

Once monthly

Once monthly
Frequency of

and to swallow monthly supervised doses in front of a

Daily once
in bracket)

leprosy worker/doctor. The importance of the regular self-

administration of the rest of the drugs in the blister pack,
Daily
WHO fixed dose regimen for PB/MB leprosy

without interruption during leprosy reactions and pregnancy,

must be explained to patients.
————————————

The efficacy of WHO-MDT has been tested time and

———————————

———————————

again. The information available to WHO, from a number of

control program, shows that the relapse rate is very low
(0.1% per year for PB and 0.06% per year for MB on
average). In addition, the low frequency of side effects has
made it highly acceptable to patients in a variety of settings.
Clofazimine

Clofazimine
Type of leprosy Drugs used

Rifampicin

Rifampicin

Unfortunately, not all centers report uniformly good

Dapsone

Dapsone

results with the MDT regimens, recommended by WHO.

Most of the problems, thus far have centered on the PB
regimen, perhaps in part due to classification problems.13 For
MB/12 months

example, some MB cases may be misdiagnosed as PB due to

PB/6 months
of treatment
& duration

erroneous counting of skin lesions if the whole body is not

Table 4

carefully examined as a result of social constraints. A patient

may have five easily visible lesions, but there might be
another small lesion or lesions at unsuspected places such as
Treatment
the natal cleft, a toe, scrotal skin, or the posterior aspect of the
elbow. In such a situation, a patient would receive only PB
treatment. Also, poor skin smear technique or insufficient
number of smears, particularly if multiple lesions are present
or because the disease is primary neuritic, may result in
misclassification and undertreatment. Similarly, morphology
of skin lesion may not match with number of skin lesions; for
example, should a patient with a four ill-defined hypopig-
mented hypoesthetic to nearly normoesthetic patches with
smooth shiny surface without loss of hair be classified as PB
or MB? Such patients may indeed relapse because they were
given inadequate therapy as a result of the incorrect diagnosis.
Studies at the Central JALMA Institute of Leprosy (CJLI),
in Agra, India, have also shown that a good number of patients
diagnosed as having PB leprosy clinically had skin smears that
were acid-fast bacilli (AFB) positive, indicating their chances
of getting inadequate treatment and these patients would be
prone for relapse.14 There is always chance of misclassifica-
tion of leprosy based on WHO recommended MB and PB
criteria. To overcome the ambiguities in the present classifi-
cation, WHO is now exploring possibilities to introduce
uniform MDT (U-MDT) with three drugs for 6 months for all
patients (discussed later).
Additionally, although WHO has stated that no toxic
effects have been reported in monthly administration of these
drugs, in a recent study a significant correlation was found
between low body mass index (BMI) and various adverse
effects (Table 2).15
Novel drugs for leprosy
With the recent development of DNA sequencing
methods, resistance to first-line (dapsone, rifampicin) drugs
have been described worldwide. In the area of patient
management, development of new drugs and new regimens
for use in situations of resistance or toxicity becomes very
important. Even though the problem of resistance is not
significant now, its potential to grow in the future should not
be underestimated.16 Various newer drugs are tabulated in
Table 5 and regimens are discussed later.
Novel treatment regimens for leprosy
Most of the present day regimens are fixed-duration
multidrug treatments (FD-MDTs) with combinations of
different drugs (Table 6).17 Although FD-MDTs have the
advantage of better compliance and have been successful in
other mycobacterial diseases like tuberculosis, their use is
not without limitations, especially in leprosy; for example,
the cure or endpoint of treatment of PB cases (smear-
negative patients) has been more difficult to define, unlike in
MB cases wherein the slit-skin smears are indicators of
disease activity. Also, continued visibility of a clinically
active patch in a proportion of patients at the end of 6 months
of therapy has been observed in almost all studies, varying
from 10% to 67%. When the duration of treatment is not long
59
enough for the body to clear the bacteria, a continued
inflammatory response results in persistent clinical activity
for up to 12 to 18 months. There is a delayed resolution in a
significant number of patients, which sometimes may turn
out to be failures of treatment. It has also been observed in a
few studies that if DDS is continued for a further period of 6
months or MDT is administered for 12 months instead of the
recommended 6 months, the proportion of patients staying
active could be significantly reduced.18
Regimens based on different combination of newer drugs for
variable duration have been analyzed in animal and human trials.
Fluoroquinolone (ofloxacin and moxifloxacin)–based
regimens
The use of fluoroquinolone (FQ) in treatment of leprosy
was discovered more than two decades ago. Previous trials
were based on rifampicin and ofloxacin (RO) administered
daily for 28 days and rifampicin, ofloxacin, and moxiflox-
acin (ROM) single-dose regimen. After failure of both these
regimens, now the thrust is on monthly administration of
ROM (intermittent therapy) for 12 months for MB and
6 months for PB. Various newer regimens can be classified
as those that are fully supervisable and those that require
daily self-administration of drugs.
Fully supervisable. Monthly administered regimens:
a. ROM combination: rifampicin 600 mg, ofloxacin 400 mg,
and minocycline 100 mg for 12 months19
b. PMM combination: rifapentine 600 mg, moxifloxacin
400 mg, minocycline 100 mg RifaPentin, Moxifloxacin,
Minocycline (PMM) for 12 months20
c. Six-week quadruple regimen: rifampicin 600 mg plus
ofloxacin 400 mg plus clofazimine 100 mg plus
minocycline 100 mg once a week for 6 weeks21
Regimens with daily self-administration of drugs:
a. Once a month, supervised rifampicin 600 mg plus ofloxacin
400 mg plus minocycline 100 mg in addition to self-
administered dapsone 100 mg plus clofazimine 50 mg daily
for 12 months22
b. Daily rifampicin 600 mg plus sparfloxacin 200 mg plus
clarithromycin 500 mg plus minocycline 100 mg for
12 weeks23
These are especially needed in rifampicin-resistant MB
patients, in whom a self-administered regimen is given in
two phases24:
a. Intensive phase: daily administration of 50 mg clofazi-
mine, together with two of the following drugs: 400 mg
ofloxacin, 100 mg minocycline, or 500 mg clarithromycin
for 6 months
b. Continuation phase: daily administration of 50 mg clofazi-
mine, together with 100 mg minocycline or 400 mg ofloxacin
for an additional 18 months
60
Fig. 1 Blister packs for pauci- and multi-bacillary leprosy: adult and pediatric kits.
Uniform MDT (U-MDT)
Uniform MDT implies a unified treatment for all patients.
All leprosy patients (PB and MB) will receive 6 months
treatment with rifampicin, clofazimine, and dapsone. WHO
in collaboration with the Global Leprosy Program (GLP)
have launched a clinical trial for comparative evaluation of
U-MDT with conventional WHO-MDT regimens for MB
and PB leprosy.25 Out of 2094 PB and 1302 MB cases, 6
relapse cases (4 among MB) were confirmed in the U-MDT
group. Rao PN et al26 have also concluded that U-MDT for 6
months was well tolerated and appeared to exert a marginal
beneficial effect in PB leprosy but was too short a regimen to
adequately treat MB leprosy.
Accompanied MDT (A-MDT)27
Accompanied MDT (A-MDT) implies providing certain
patients with a full course of treatment on their first visit to
the leprosy clinics after diagnosis. It was recommended by
WHO to serve populations such as those living in hard-to-
reach border areas, in urban slums, or in areas of civil strife
and those working as migrant laborers.
Immunotherapy
The hunt for a vaccine as a weapon for primary prevention
of leprosy is still going on. Various drugs and biologicals,
which have been tried as immunotherapeutic and immuno-
prophylactic agents in leprosy, are based on cultivable
mycobacteria, such as Indian Cancer Research Centre
(ICRC) bacillus, Mycobacterium w (Mw), Mycobacterium
H.K. Kar, R. Gupta
habana, bacillus Calmette-Guérin (BCG), Mycobacterium
vaccae, and drugs like levamisol and zinc. Of these, Mw and
BCG are the most well studied. Theoretically, the Mw
(renamed as Mycobacterium indicus pranii, after elucidation
of the full genome) vaccine acts by mediating the release of
various cytokines and chemokines, especially CXCL10 (IP-
10) and CXCL11 (I-TAC), which are involved in stimulation
of T-cell migration and natural killer cells. When given along
with MDT in patients with multibacillary leprosy, it results in
faster clearance of dead bacilli from the body and thus may be
helpful in preventing the occurrence of leprosy reaction;
unfortunately, in previous clinical trials, results were
notwithstanding with this expectation. 28 In a recent
study, prior immunization with Mw has been endowed as
a good immunomodulator and did augment the effect of
chemotherapy.29
The status of BCG as a vaccine for leprosy is still not
clear due to the heterogeneity of populations studied. A
meta-analysis of published data may determine the efficacy
of BCG protection on leprosy. 30 In the light of the results,
they argue for more emphasis on the role of BCG
vaccination in leprosy control and research. Lately, the
trial comparing protective efficacies of Mw immunization
in both live and killed forms through the parenteral route
and by aerosol immunization with that of BCG found Mw
immunization to be superior by both the parenteral route
and aerosol administration in the mouse model. 31 Another
recent trial conducted to assess the impact of repeated or
booster BCG vaccinations against leprosy did not give
encouraging results.32
Treatment
Table 5 Novel drug for treatment of leprosy
Drug Mechanism of Action
45
Fluoroquinolone Inhibit the bacterial DNA gyrase, thereby
inhibiting the coiling and super-coiling of DNA. rapid; a 1000 fold decrease in viable colony forming
Minocycline45 Acts by binding to the 30s ribosomal subunits
of bacteria, thereby inhibiting protein synthesis. studies have shown complete killing within 4 weeks.
Clarithromycin45 Inhibiting protein synthesis by binding to 50s
ribosomal subunits
Ansamycins (rifapentin, Semisynthetic derivative of Rifampicin
isobutylpiperazinyl
Rifampicin)45
Fusidic acid45 Acts via inhibiting bacterial protein
synthesis by preventing the translocation
of elongation factor-G from the ribosomes.
Brodimoprim and Inhibit dihydrofolate reductase
Epiroprim45
PH-22 AND PQ-2245 Derivatives of thiacetazone
(inhibits cyclopropanation of cell
wall mycolic acids in mycobacteria).
Deoxy Fructo Serotonin Unknown
(DFS)45
Role of surgery
After having achieved the goal of elimination, it is felt that
prevention and treatment of deformities and disabilities should
be given importance so as to decrease the stigma associated
with this disease and to facilitate the social and psychological
rehabilitation of persons affected by leprosy. The reconstruc-
tive procedures (RCS) are carried out at the RCS unit of a
tertiary level hospital; the plastic surgeon, orthopedic surgeon,
and physiotherapy technician examine patients with visible
deformity like claw hand and lagophthalmos and decide who
would benefit from surgeries, the majority of which are based
on tendon transfer operations. This topic is beyond the domain
of this chapter.
Recent developments
Most of the recent research is focused on discovering and
verifying new regimens for the treatment of leprosy that are
shorter in duration and at the same time equally or even more
efficacious to deal with problems of drug resistance and
relapse. One group studied the use of multidose ROM
(rifampicin, ofloxacin, and minocycline) as an alternative
treatment to WHO-MDT comprising rifampicin, clofazimine,
and dapsone.33 They emphasized that the adverse effects of the
current MDT regimen are probably underestimated and stated
that this new regimen would reduce the common adverse
effects, including dapsone-induced hemolytic anemia and
clofazimine-induced pigmentation; moreover, ofloxacin and
minocycline have been shown to be more bactericidal than
61
Comment
No cross-resistance with any drug. Action is extremely
units (CFU) is achieved within in 1-3 hours.
Highly lipophilic bacteriostatic drug. Mouse footpad
Achieve high intracellular concentration → prevent the
selection of resistant bacilli. Sequential blockage of
protein synthesis by Minocycline and Clarithromycin,
a marked synergism of action has been found.
Advantage over Rifampicin 1) longer half-life 2)
lower MIC, 3) effective against Rifampicin resistant strains.
has high lipophilicity, with resultant
higher intracellular concentration
Bactericidal drug. Active against Dapsone-resistant strains.
Bacteriostatic. Added advantage of synergism with
Dapsone and Rifampicin
Kill bacilli within Schwann cells and macrophages.
Protect nerve damage and decrease attachment
of M. leprae by the cultured Schwann cells.
dapsone and clofazimine in both mice and clinical trials. The
single monthly dosing might improve compliance, which is
also a major challenge.
A recent systematic review34 has assessed all the studies
comparing ROM and MDT and found 14 studies that could be
included in the review. Four of these compared single-dose
ROM with WHO-MDT for treating paucibacillary leprosy;
combining these studies it was found that single-dose ROM is
slightly less effective than WHO-MDT, with a relative risk of
0.91 (95% confidence interval [CI] 231%) but still has a very
high cure rate. Only two studies have been reported using
multiple doses of ROM in lepromatous leprosy (LL). One of
them was from the Philippines by Villahermosa et al35; they
compared 21 borderline leprosy (BL) and LL patients who were
given either monthly ROM (n = 10) or the standard MDT (n =
11) for 24 months. These patients had a mean bacterial index
(BI) of 4 (range 2.7-5.1) at entry to the study, which fell to 1.18
(range 0-3.5). No toxicities were recorded in patients receiving
ROM, whereas all patients on WHO-MDT developed
clofazimine-induced pigmentation. These are important and
encouraging results that should be repeated on a larger scale
with a randomized design.
The effectiveness of ofloxacin alone and in combination
with WHO-MDT in MB leprosy has been studied A total of
198 MB patients were recruited to participate in a randomized,
double-blind trial. Among those, 53 patients were treated with
1 year of WHO-MDT, 55 patients received 1 year of WHO-
MDT plus an initial 1 month of daily ofloxacin, and 63 patients
were treated with 1 month of daily rifampicin and daily
ofloxacin, whereas 27 were treated with 2 years of WHO-
62 H.K. Kar, R. Gupta

Table 6 Evolution of various treatment regimens in treatment of leprosy

S.NO Regimen Year of Duration Remarks
'launch
1. DDS monotherapy 1960 to 1980 Lifelong High chances of emergence of secondary drug resistance
(continuous)
2. WHO-MDT 1981 to 1983 24 months Initially all smear positive MB cases were administered
{recommended by NLEP)45 or till skin Rifampicin daily for 21 days (intensive therapy) followed by
smear negativity monthly pulse dose. This was done to ensure early disinfection
of MB cases to render them non-infectious to community.
3. WHO-MDT (FDT-24)24 1994 24 months (daily) Monthly supervised pulse dose of Rifampicin was considered
optimal based on the fact - the drug possesses significant activity;
even when given intermittently d/t very long post antibiotic effect.
4. WHO-MDT (FDT-12 for 1997 12 months for MB Based on observation of BLP and WHO on FDT-12/6 for
MB and FDT-6 for PB)11 and 6 month for PB MB/PB group, no. of relapses were found to insignificant
compared to the cost of FDT-24.
5. ROM-12 for MB/ROM-6 1995 12 months Objective behind this regimen was to make the chemotherapy
for PB (monthly) of leprosy simpler and operationally feasible for mass programs
and to ensure better treatment compliance. Results of intermittent
ROM therapy vs FDT-24, FDT-12/6are awaited.45
6. RO a 1992 28 days (daily) A recent report by WHO shows that in Brazil, high relapse
rate of 38.8%, was observed in the group treated with RO
for one month after five years of follow-up.45
7. ROM-1 1997 1 day (single dose) WHO compare the efficacy of ROM with that of the WHO
PB-MDT in patients with one skin lesion and no peripheral
nerve trunk involvement. At 18 months follow-up, complete
cure was observed in 46.9% of the ROM group as against
54.7% in WHO PB-MDT. Hence, ROM for single skin
lesion leprosy was withdrawn from the program.45
8. PMMX-1 b 2000 1 day (single dose) Moxifloxacin is the most powerful bactericidal agent.
In clinical trials by Ji and Grosset in 2000,45 Moxifloxacin
was proved to be highly effective.
a
RO stands for Rifamipicin and Ofloxacin.
b
Mx stands for Moxifloxacin.

MDT. Patients were regularly monitored for signs of relapse
for at least 7 years after being released from treatment. Relapse
occurred at a higher rate (p b .001) in those treated with a 1-
month regimen alone, whereas in the other three regimens that
included WHO-MDT it ranged from 0% to 5%. This study
found that a short-course treatment for MB patients with a
rifampicin-ofloxacin combination had a higher failure rate.
The addition of 1 month of daily ofloxacin to 12 months MB
WHO-MDT did not increase its efficacy.36
Another randomized controlled trial assessed the effect of
adding clarithromycin to rifampicin, ofloxacin, and mino-
cycline (C-ROM) in the treatment of single-lesion pauciba-
cillary leprosy. Three hundred patients with single-lesion
leprosy but no nerve thickening were randomly allocated
(using a random number table) to two treatment groups, 151
to ROM and 149 to C-ROM. All patients were given a single
dose of ROM or C-ROM and followed up every 6 months for
disease status, cure rate, reaction, and relapse. The cure rate
at 2 years was 93.1% in the ROM group and 91.4% in the C-
ROM group. By this time three relapses had occurred in the
ROM group, whereas two patients were found to have
relapsed in the C-ROM group; thus, there was no statistical
difference in relapse rates (2.1% versus 1.41%, P ¼ .287) in
the two groups. The study showed that addition of
clarithromycin to ROM does not significantly improve the
efficacy as measured in terms of cure rates and relapse rates
in leprosy patients with a single skin lesion. 37
Recently, the efficacy of linezolid and gatifloxacin were
assessed in a mice model of leprosy.38 Gatifloxacin was
bactericidal, like other FQs, whereas finezolid was bacterio-
static at a dose of 25 mg/kg and progressively more bactericidal
at doses of 50 mg/kg and 100 mg/kg. No antagonisms were
detected between these drugs when used in combinations.
These agents should be further studied alone and in
combination with established antileprotic drugs to sprout a
new regimen in the pipeline.
With the elucidation of the role of vitamin D as an
immunomodulator, a number of studies have appeared to look
for its role as an adjuvant in treatment of leprosy. Vitamin D
helps in induction of T helper type 1 cells (Th1) that assist the
immune system in acquiring “memory.” Recently researchers
compared the micro-RNAs (miRNA) in human skin lesions
from two types of leprosy, tuberculoid and lepromatous. They
found that M leprae can actually regulate the host’s cellular
Treatment
miRNA profile at the site of the infection to interfere with the
antimicrobial response. Human monocytes, or macrophages,
infected with M leprae express the miRNA hsa-mir-21, which
actually blocks the nascent T cell’s gene that would otherwise
activate when vitamin D is present, preventing the transfor-
mation into Th1 cells. With this discovery, researchers
recognized a potential therapeutic approach that doesn’t rely
on administering drugs toxic to M leprae, but rather
administering anti–has-mir-21 to help counter the overexpres-
sion of hsa-mir-21 induced by M leprae, together with vitamin
D supplementation.39
Another area of recent research is evaluation of U-MDT
in all aspects, including efficacy, side effects, and frequency
of reaction. One group40 investigated the changes of
bacteriologic index and leprosy reactions among MB
patients treated with U-MDT. A total of 166 patients were
recruited for the U-MDT trial. All patients were followed up
once a year for 3 years after completion of treatment. There
was a significant decrease in the mean BI, and 73.5% of
patients treated with U-MDT became BI negative during 3
years of follow-up. These results support the possibility of
use of UMDT in the field; however, the frequency of type 1
reaction seemed a little higher, but the numbers of patients
enrolled were too few to determine statistical significance.
Similar increase in frequency of reaction was also noted in an
open-label randomized controlled clinical trial evaluating the
association of the treatment (U-MDT) duration with the
frequency of reactions among MB patients with high
bacillary load (BI N 3).41
Another group conducted a quantitative, prospective,
nested study to verify the correlation between leprosy types
and the adverse effects of drugs. Forty patients with
tuberculoid leprosy (TT) were selected. Twenty patients
followed a standard therapy of dapsone and rifampicin and
20 were administered dapsone, rifampicin, and clofazimine
(U-MDT). Twenty patients with borderline lepromatous
(BL) and lepromatous leprosy (LL) were also selected and
treated with U-MDT. With the exception of hemolytic
anemia, there was a low incidence of adverse effects in all the
groups. The highest incidence of hemolytic anemia was in
the PB (95%) and MB groups (100%) treated with MDT-
MB. A comparison to the PB patients who were treated with
MDT-PB (65%, p b .05) suggests a role for clofazimine in
developing these adverse effects. Researchers did not
observe any differences in the incidence of hemolytic anemia
or other side effects across groups of patients with TT, BL, or
LL treated with U-MDT.42
In spite of multiple reports on resistance and relapse from
various parts of the world, WHO-MDT has stood the test of
time and is still highly efficacious, as demonstrated by
Maghanoy et al in 2011. Smear-positive MB patients treated
with WHO-MDT for 1 year were followed up at yearly
intervals, during which they underwent slit-skin smear
examination and were clinically monitored for possible signs
of relapse. Of 300 patients recruited, only one case of relapse
was detected after 7 years, with an absolute relapse rate of
63
0.3% (0.52 per 1000 patient-years at risk [PYAR]); These data
provide strong evidence in favor of the long-term efficacy of
the 1-year WHO-MDT for MB leprosy patients, even in those
with a high initial BI.43
“Prevention is always better than cure.” In accordance
with this dictum, there is resurgence in the search for better
immunoprophylactic agents for leprosy in the recent era.
After failure of various killed vaccines for leprosy, Geluk et
al44 investigated the role of subunit vaccines for M leprae
infection. They found p113-121, derived from M leprae
protein ML1419c, induced significant interferon γ (IFN-γ)
production by CD8+ T cells in 90% of paucibacillary leprosy
patients and 80% of multibacillary patients' contacts,
demonstrating induction of M leprae–specific CD8+ T-cell
immunity. Most CD8+ T cells produced IFN-γ, but distinct
IFN-γ–positive/tumor necrosis factor α (TNF-α)–positive
populations were detected simultaneously with significant
secretion of CXCL10/IP-10, CXCL9/MIG, and VEGF.
Strikingly, peptide immunization also induced high
ML1419c-specific immunoglobulin G (IgG) levels, strongly
suggesting that peptide-specific CD8+ T cells provide help to
B cells in vivo because CD4+ T cells were undetectable.
These data suggest that ML1419c p113-121 induces potent
CD8+ T cells that provide protective immunity against M
leprae and B-cell help for induction of specific IgG,
suggesting its potential use in diagnostics and as a subunit
(vaccine) for M leprae infection.
With the identification of Toll-like receptors as a
component of innate immune response, their role in various
disorders is being rapidly evaluated. Investigators recently
demonstrated that combining ML0276 (a M leprae–specific
protein) with a Toll-like receptor 4 (TLR4) (EM005), TLR7
(Imiquimod), or TLR9 (CpG DNA) agonist during
immunization induces T h1 responses that limit local
inflammation upon experimental M leprae infection via
release of IFN-γ. Despite the potent Th1 response induced
by this regimen, it could not provide protection in terms of
limiting bacterial growth. They concluded that EM005 is the
most potent adjuvant for stimulating a Th1 response and
indicate that although a subunit vaccine containing the
ML0276 protein may be useful for the prevention of
immune pathologic conditions during leprosy, it will not
control bacterial burden and is therefore unlikely to
interrupt disease transmission.45
Conclusions
WHO-MDT is the gold standard treatment of leprosy;
however, newer drugs, especially fluoroquinolones, have
also shown excellent efficacy against M leprae, and hence
there is sufficient evidence for further analysis for various
newer treatment regimens containing one of the FQs on
much larger scale with the aim to incorporate them into the
National Leprosy Eradication Program. In spite of a
significant amount of data on usefulness of shorter duration
64
and once-a-month fully supervised regimens in treatment of
leprosy, there is still a risk of increasing relapse, hence their
introduction in the field needs more substantiation.
As far as an introduction of U-MDT is concerned, it
appears to be a promising tool in areas where classification of
leprosy is based on clinical criteria alone due to scarcity of
laboratory-based confirmatory techniques, but the increased
risk of reaction must always be kept in mind. We are yet to
receive the final WHO data on the efficacy of U-MDT
conducted in India and other countries. It is probably critical
in leprosy chemotherapy to give sufficient antibiotic
treatment over long enough duration. The slow metabolism
of M leprae probably requires several hits over a long
duration to achieve a sufficient kill. This is evident from high
relapse rates after the WHO sponsored 4-week course of
MDT. As of now, there is no consensus guideline on use of
leprosy vaccines as an immunotherapeutic agent due to the
ambiguity of results obtained from previous studies;
however, recent research focusing on peptide immunization
appears to be a promising tool that should be further
evaluated in large-scale human trials.
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