REVIEWS

OF

THERAPEUTICS

Hansens Disease (Leprosy): Current and Future

Pharmacotherapy and Treatment of Disease-Related
Immunologic Reactions
Davey P. Legendre, Pharm.D., Christina A. Muzny, M.D., and Edwin Swiatlo, M.D., Ph.D.
Hansens disease, also known as leprosy, remains an important public health
problem throughout the world, including North America. The causative
microbe in Hansens disease is Mycobacterium leprae, an acid-fast organism that
is difficult to grow in vitro. The nine-banded armadillo is the major animal
reservoir in the United States. Manifestations of disease vary based on host
immune response and can range from tuberculoid to lepromatous leprosy
(paucibacillary to multibacillary disease). Hansens disease typically affects the
skin, nerves, and eyes, and patients may present with skin lesions, weakness,
numbness, eye pain, or loss of vision. Definitive diagnosis is based on a combination of physical examination findings and skin biopsy and/or smear. Modern
antibacterial therapy typically consists of combinations of dapsone and rifampin
with or without clofazimine. Clofazimine is available only as an investigational
drug through the National Hansens Disease Program. Other options include
moxifloxacin, ofloxacin, minocycline, and clarithromycin. Hansens disease is
associated with type 1 (reversal) and type 2 (erythema nodosum leprosum)
immunologic reactions, during which the disease process appears to worsen
dramatically. These reactions may occur at any time before, during, or after
treatment. Antibacterial therapy should usually be continued during these
reactions. Treatment options for these reactions differ based on clinical manifestations and include corticosteroids, thalidomide, pentoxiphylline, tumor necrosis
factor inhibitors, and T cell inhibitors. Prompt diagnosis, antimicrobial therapy, and treatment of reactions dramatically reduce complications of the disease.
Key Words: Hansens disease, leprosy, reversal reaction, erythema nodosum
leprosum, ENL.
(Pharmacotherapy 2012;32(1):2737)
OUTLINE
Epidemiology
Microbiology
Pathogenesis
Clinical Manifestations
Diagnosis
Immunologic Reactions
Treatment of the Disease
Dapsone
Rifampin
Clofazimine
Fluoroquinolones
Minocycline

Clarithromycin
Future Therapy
Prevention
Treatment of Immunologic Reactions
Corticosteroids
Thalidomide
Pentoxiphylline
Tumor Necrosis Factor Inhibitors
T-Cell Inhibitors
Adjunctive Therapy
Conclusion

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PHARMACOTHERAPY Volume 32, Number 1, 2012

Hansens disease, also known as leprosy, is an

ancient infectious disease, with references dating
back to Biblical times.1 Recent research suggests
that individuals have been afflicted with this
disease dating back as early as 1550 B.C.2
Throughout the course of history, Hansens disease has played a significant role in the lives of
mankind as a feared, misunderstood, and disfiguring disease for which no treatment was available.2 Infected persons were forced to live in
secluded leper colonies, until the 1940s when
modern antibacterial therapy became available,
due to concern for contagiousness and lack of
effective treatment.2 Mycobacterium leprae, the
causative agent of this disease and the first
human pathogen to be described, was identified
in 1873 by Dr. Armauer Hansen of Norway.2
Because of Hansens discovery, successful efforts
to characterize the disease and find treatments
that would slow or eliminate its progression
were pursued.

sens Disease Registry in 2008.5 The annual

number of endemic cases reported in the United
States has remained relatively stable since 1988.
The incidence of disease peaks in the age groups
of 1015 and 3060 years, and the male:female
ratio of infection is ~2:1.1 No racial predilection
for acquisition of this disease is known.
Humans are the primary reservoir for M. leprae.
Besides man, only wild nine-banded armadillos
(Dasypus novemcintus) are known to be natural
hosts of M. leprae.6 Several cases of suspected
zoonotic transmission from armadillos to humans
have been reported.710 Infected armadillos have
been found in Alabama, Arkansas, Louisiana, Mississippi, Texas, and Mexico.11 Whole-genome
sequencing of M. leprae from infected wild armadillos and patients with leprosy in the United
States has revealed a unique M. leprae genotype
(3I-2-v1) that has not been reported elsewhere in
the world, lending further evidence to the hypothesis that M. leprae is a zoonosis in this region.12

Epidemiology

Microbiology

Hansens disease occurs in both tropical and

subtropical temperate climates. Worldwide, it
remains an important public health problem,
especially in Asia, Africa, and South America,
including India, Brazil, Indonesia, Democratic
Republic of the Congo, Bangladesh, Nepal,
Angola, China, Madagascar, Mozambique, Nigeria, the Philippines, and the United Republic of
Tanzania.3 Nevertheless, the annual case detection rate of new infections with M. leprae has
declined over the past decade as a result of more
intensive infection control programs and the use
of multidrug therapy.3 In the United States,
immigrants from endemic countries constitute
the vast majority of cases diagnosed annually
(8595%).4 Endemic foci do exist, however,
mainly in parts of Texas, Louisiana, Florida, and
California.5 A total of 150 endemic cases in the
United States were reported to the National Han-

Although M. leprae cannot be cultured in

synthetic laboratory media, it does infect ninebanded armadillos and multiplies in mouse footpads. These animal hosts have provided
sufficient quantities of bacteria for microbiologic
investigations. The organism is an aerobic rodshaped bacterium that is acid fast with carbol
fuchsin and other commonly used bacterial
stains.
The cell wall of M. leprae is structurally similar to that of most Mycobacterium species. The
polymers that lie adjacent to the cytoplasmic
membrane comprise a complex amalgam of
polysaccharides and glycolipids. Mycolic acids
constitute up to 60% of the cell wall by weight
and are thought to be primarily responsible for
the acid-fast staining characteristic of mycobacteria. The outer surface of the cell wall contains
surface-exposed proteins that are unique to each
species. The complex mixture of polysaccharides
and glycolipids renders mycobacterial cells
impermeable to most solutes without specific
transport mechanisms. Resistance to both cellular and humoral immune responses is attributed,
in large part, to the complex cell wall of pathogenic mycobacteria.13
Little is known about the physiology of
M. leprae, but its doubling time of nearly
14 days in vivo is the longest of any known
pathogen. The complete genome of a strain of
M. leprae isolated in the Indian state of Tamil

From the Pharmacy Division, Health Management

Associates, Woodstock, Georgia (Dr. Legendre); the Division
of Infectious Diseases, University of Alabama at Birmingham,
Birmingham, Alabama (Dr. Muzny); and the Division of
Infectious Diseases, University of Mississippi Medical Center,
Jackson, Mississippi (Dr. Swiatlo).
For reprints, visit https://caesar.sheridan.com/reprints/
redir.php?pub=10089&acro=PHAR. For questions or comments, contact Davey P. Legendre, Pharm. D., BCPS-AQID,
Health Management Associates, Pharmacy Division, 5811
Pelican Bay Blvd., Suite 500, Naples, FL 34108.

TREATMENT OF HANSENS DISEASE Legendre et al

Nadu has been published.14 The genome is
~3.2 Mbp and has a G + C content of 57.8%,
compared with a G + C content of 65.6% in Mycobacterium tuberculosis. Although M. leprae and M.
tuberculosis appear to have originated from a
common ancestor, the M. leprae genome is ~30%
smaller and contains over 1000 pseudogenes
that have functional full-length homologues in
M. tuberculosis. It appears that less than half the
genome of M. leprae is protein-coding sequence.
Many metabolic pathways found in other Mycobacterium species, including respiratory electron
transport systems, are lacking in M. leprae, and
its ability to generate energy in the form of
adenosine triphosphate (ATP) is severely compromised.14
Pathogenesis
The mode of transmission of M. leprae has not
been absolutely proven; however, the most common mechanism is thought to occur through the
respiratory route in a manner similar to that of
tuberculosis. Inoculation of bacilli through broken skin and other close physical contact has also
been implicated. In the southeastern United
States, armadillos carry M. leprae, and contact
with these animals is presumed to cause some
infections in this region. Most people are resistant to infection with M. leprae; however, certain
genotypes are increasingly recognized as risk factors for leprosy. Both human leukocyte antigen
(HLA) and non-HLA alleles have been linked to
susceptibility to infection.15 A recent genomewide association study in eastern China associated variant genes in the NOD2 signaling
pathway with susceptibility to infection with
M. leprae.16
The pathogenesis of infection with M. leprae
is poorly understood, but most evidence suggests
that clinical manifestations of infection result
primarily from host immune responses to the
leprosy bacillus. Classified on the basis of the
Ridley-Jopling scale or by the World Health
Organization (WHO), the immune response to
M. leprae varies over a large continuum and is
thought to be responsible for the heterogeneous
clinical appearance of leprosy.1719 The RidleyJopling scale combines clinical, immunologic,
and histopathologic evidence and recognizes five
forms of leprosy: tuberculoid, borderline tuberculoid, midborderline, borderline lepromatous,
and lepromatous leprosy. The WHO classification scheme is superimposed on the RidleyJopling scale to fit two distinct multidrug

29

therapy regimens and consists of two broad categories: paucibacillary disease, which includes the
tuberculoid and borderline tuberculoid forms,
and multibacillary disease, which includes the
midborderline, borderline lepromatous, and
lepromatous forms (Figure 1).
At the paucibacillary tuberculoid end of the
spectrum, skin and nerve lesions have characteristics of well-developed T helper cell type 1 (Th1)
mediated immune responses and possess few
acid-fast bacilli that signify presence of the organism. This form of leprosy typically is associated
with a low burden of organisms and few skin
lesions. In contrast, at the multibacillary lepromatous end of the spectrum, Th2-type cellular
immune responses predominate, with numerous
skin lesions containing many acid-fast bacilli.
This form of infection results in multiple progressive skin lesions and may extensively involve
peripheral nerves. Between these two phenotypic
extremes is a highly variable continuum of clinical disease that is marked by dynamic immunologic responses to M. leprae.
The clinical manifestations of infection in an
individual may evolve in a waxing and waning
manner dependent on the predominant immunologic response at any time. These clinical forms
of infection have been studied in the context of
gene expression profiling,20 and this approach
has uncovered new insights into the mechanisms
underlying the regulation of disparate immune
responses to M. leprae.
Clinical Manifestations
Because of the large variability in host
immune response to M. leprae, patients present
Borderline disease
TT

BT

BB

BL

LL

Unstable clinical presentation

CMI

Paucibacillary

AFB

Multibacillary

Figure 1. Relationships of bacterial burden, immune

response, and clinical classification schemes. The five forms
of leprosy based on the Ridley-Jopling Scale are tuberculoid
(TT), borderline tuberculoid (BT), midborderline (BB),
borderline lepromatous (BL), and lepromatous (LL).
CMI = cell-mediated immunity; AFB = acid-fast bacilli.

30

PHARMACOTHERAPY Volume 32, Number 1, 2012

with heterogeneous clinical manifestations of

disease. The period between infection and overt
disease varies widely from several months to 30
40 years.1 The disease typically affects the skin,
nerves, and eyes, and patients may present with
skin lesions, weakness or numbness, eye pain,
or loss of vision. The clinical diagnosis of leprosy should always be suspected in someone
with skin lesions and/or enlarged nerves accompanied by sensory loss.1719
At the paucibacillary tuberculoid end of the
spectrum of disease, patients can have one to several large asymmetric skin lesions, typically macules or plaques, with sharply defined borders
and hypopigmented, anesthetic centers. In borderline tuberculoid, the most common form of
leprosy, skin lesions resemble those of tuberculoid leprosy but are more frequent and variable
in appearance with less well-demarcated borders.
Asymmetric enlargement of peripheral nerves
and progressive nerve damage are common, and
patients may present with muscle weakness or
trauma secondary to sensory impairment. Progressing toward the multibacillary lepromatous
end of the spectrum, patients with the midborderline form are immunologically unstable and
may shift rapidly toward the borderline tuberculoid end of the spectrum during a reversal reaction (Figure 1). Skin lesions are numerous; vary
in size, shape, and distribution; and may be hypopigmented or erythematous.
A characteristic target lesion, typically present in patients with the midborderline form of
leprosy, has a broad, erythematous border with a
vague outer edge and a punched-out pale center
with sensory impairment. Patients with the borderline lepromatous form also have numerous
skin lesions, generally with intact sensation,
although occasionally lesions may exhibit
hypoesthesia. Patients at the lepromatous end
of the disease spectrum have extensive disease
and widespread involvement of the skin and
other organs. Generalized infiltration of the
dermis may cause the skin to have a smooth,
shiny appearance. Numerous skin lesions
(macules, papules, or nodules) are symmetrically distributed, but with retained sensation.
Progressive thickening of the skin causes
coarse facial features and thickening of the
ear lobes. Eyebrows and eyelashes are thinned
out, and infiltration of the nasal mucosa may
occur, resulting in discharge and obstruction.
Erosion of the cartilage and nasomaxillary
bones can result in perforation of the nasal
septum, collapse of the nose, and saddle-nose

deformity. Extension into the eye can cause

keratitis and iritis. Infiltration of dermal
nerves can cause peripheral sensory loss. 17, 18
Diagnosis
More than 125 years after the discovery of M.
leprae, the bacillus is yet to be cultivated in vitro.
The diagnosis of leprosy is based on a combination of physical examination findings and skin
biopsy and/or smear.17, 18 Slit-skin smears can
be performed by making a shallow incision in
the skin at standard sites (bilateral earlobes,
elbows, and knees), as well as from several typical skin lesions. After the incision is made, the
inner surface of the wound is scraped with a
blade held at a right angle to the incision. Upon
scraping, tissue fluid and dermal tissue are
obtained and transferred to a clean microscopic
slide where a circular smear is made. After the
slide is stained with ZiehlNeelsen carbol-fuchsin and counterstained with methylene blue, the
number of acid-fast bacilli viewed under the
microscope per oil immersion field is determined and expressed as a bacteriologic index.
This technique may be used to guide multidrug
therapy by assessing the bacterial load before
and during therapy.
In addition, a full-thickness skin biopsy
specimen from the margin of an active lesion
can be obtained and the Fite stain used to visualize acid-fast bacilli in the tissue. If another
mycobacterial infection is suspected, culture of
tissue biopsy material can be performed; growth
will exclude M. leprae. Also, a rapid molecular
assay using real-time polymerase chain reaction
to identify and quantify M. leprae DNA in tissue
samples can be performed at laboratory facilities
equipped to perform this test, such as the
National Hansens Disease Program (NHDP)
Laboratory in Baton Rouge, Louisiana.21, 22
Immunologic Reactions
Immunologic reactions to M. leprae antigens
are generally classified as either type 1 (reversal)
or type 2 (erythema nodosum leprosum
[ENL]) and reflect the predominant immunologic response locally in either nerves or skin.
An example of a type 1 (reversal) reaction is
shown in Figure 2. Approximately one third of
patients with borderline leprosy are at risk for
type 1 reactions, whereas type 2 reactions affect
50% of patients with the lepromatous form
and 10% of those with the borderline leproma-

TREATMENT OF HANSENS DISEASE Legendre et al

Figure 2. Example of a type 1 (reversal) reaction to

therapy for Hansens disease (leprosy) appearing as skin
lesions on the patients back.

tous form of leprosy. These reactions may be a

presenting feature of the disease or occur during
or after multidrug therapy.23 These reactions
have also been described in patients with human
immunodeficiency virus as part of the immune
reconstitution inflammatory syndrome.24 Prompt
recognition and treatment of inflammatory reactions are necessary to minimize progressive
nerve damage that can occur with sustained
inflammatory responses.
Type 1 reactions are characterized by a shift
to Th1-type immune responses in the host and
are associated with locally elevated levels of
interferon-c, tumor necrosis factor-a (TNF-a),
interleukin-12, and inducible nitric oxide synthase.25 This type of reaction can be seen in
any type of leprosy but is uncommon in the
tuberculoid form of the disease as an appropriate Th1-type immune response already exists.
The diagnosis of type 1 reactions is generally
made clinically; however, skin biopsy is often
useful. Histologic criteria for type 1 reactions
are not standardized, but common findings
include dermal edema, large epithelioid granulomas, and plasma cells.26 Skin lesions may
become larger and more erythematous and may
ulcerate. New or worsening symptoms of neuritis may appear and can include both motor and
sensory nerve dysfunction.23 Generalized edema
may occur, but systemic symptoms are not
common.
Type 2 reactions, also known as ENL, are distinguished clinically by fever, malaise, and the
rapid appearance of new subcutaneous nodules
that are erythematous and quite painful.17 These
lesions are typically found on the face and exten-

31

sor surfaces of the limbs, but any site of the body

can be affected.23 Painful neuritis is a common
complication. Erythema nodosum leprosum is
thought to be an immune complex disease with
consequent activation of complement. Circulating levels of TNF-a and interferon-c are elevated.27 Widespread immune complex deposition
can occur and cause polyarthritis, iridocyclitis,
orchitis, lymphadenitis, and glumerulonephritis.17
Peripheral leukocytosis with neutrophils is a common laboratory finding. Patients with borderline
or the lepromatous form of leprosy are at highest
risk for ENL because they have a higher bacteriologic index.23
A rare but potentially life-threatening reaction
to M. leprae is erythema necroticans or Lucios
phenomenon.28 This reaction is distinct from
type 1 and 2 reactions and is characterized by
necrotizing vasculitis that has been ascribed to
invasion of vascular endothelium with M. leprae.
Clinical manifestations include bluish or violaceous and hemorrhagic plaques, followed by
necrotic ulcerations. These symptoms typically
occur in the absence of systemic complaints or
leukocytosis. The precise role of dysregulated
immune responses in this reaction has not been
fully studied.
Treatment of the Disease
Before the advent of sulfone treatment, therapy
for Hansens disease consisted of potassium
iodide, arsenic, antimony, copper, sera, vaccines,
aniline dyes, thymol, strychnine, baths, X-rays,
radium, and electrical current.29 Chaulmoogra
oil, a product of the seeds of several species of
the Hydnocarpus tree, was a hallmark of therapy
in the late 19th and early 20th centuries, with
varying reports of documented success and
indifferent results. The oil was mixed with lard
and applied locally as well as taken orally several times/day.30 Commercial preparations of
chaulmoogric acid became available in 1909 by
Bayer and Company under the name Antileprol
and later Chaulmestrol (Winthrop Chemical
Company).31 Oral therapy appeared to be the
most effective, but the dosage had to be titrated
over time primarily because of nausea. The drug
was also prepared as an injection, but the
adverse effects of fever, local reactions, and
abscess made therapy difficult to tolerate.
In his book Alone No Longer, Stanley Stein, a
pharmacist who contracted Hansens disease,
filled capsules of foul smelling oily liquid that
left him so nauseated that [he] quickly recorked

32

PHARMACOTHERAPY Volume 32, Number 1, 2012

Table 1. Recommended Therapy According to the World Health Organization33 and the National Hansens Disease Program34
WHO
Classification of
Disease
NHDP Recommendation
WHO Recommendation
Single-lesion
paucibacillary
Paucibacillary
Multibacillary

Dapsone 100 mg/day + rifampin 600

day for 12 mo
Dapsone 100 mg/day + rifampin 600
day for 12 mo
Dapsone 100 mg/day + rifampin 600
day + clofazimine 50 mg/day for 24

mg/
mg/
mg/
mo

Rifampin 600 mg once + ofloxacin 400 mg once

+ minocycline 100 mg oncea
Dapsone 100 mg/day (unsupervised) + rifampin 600 mg/mo
(supervised) for 6 mo
Dapsone 100 mg/day (unsupervised) + rifampin 600 mg/mo
(supervised) + clofazimine 300 mg/mo (supervised) for
24 mo

WHO = World Health Organization; NHDP = National Hansens Disease Program.

a
This regimen is not recommended in the United States and is associated with clinical failure.

Table 2. Pharmacokinetic Properties of Antibacterials3638

Antibacterial
Bioavailability (%)
Half-Life (hrs)
Dapsone
Rifampin
Clofazimine
Ofloxacin
Moxifloxacin
Minocycline
Clarithromycin

8099
6099a
2070b
98
86
100
55

30
35
70 days
48
15
1418
3

Metabolism

Route of Elimination

Acetylation
Deacetylation
Not available
Hepatic
Glucoronidation, sulfation
Hepatic
Hepatic

20% urine
60% feces, 30% urine
Feces
95% urine, 5% feces
20% urine, 25% feces
20% urine
30% urine

Food decreases absorption.

Food increases absorption.

the bottle.32 Ironically, he distributed pills in

the cafeteria at the leprosarium in Carville, Louisiana. He also described a chaulmoogra oil injection combined with olive oil and benzocaine that
left painful suppurating abscesses and resulted
in several hospitalizations.32
Although modern recommendations for therapy differ between the U.S. Public Health Service
NHDP and the WHO, antibacterials targeting
M. leprae are the mainstay of therapy. Table 1
shows recommendations for therapy, noting
WHO suggestions for directly observed therapy.3335 Pharmacokinetic properties of the
antibacterials are listed in Table 2.3638
Dapsone
Sulfones have long been the cornerstone for
treatment of Hansens disease. Dapsone exerts
weakly bactericidal activity against M. leprae by
inhibiting dihydropteroate synthase, ultimately
preventing folic acid synthesis. In a mouse footpad model, oral dapsone therapy killed 99.4% of
viable organisms as evidenced by a lag of an
average of 78 days for M. leprae growth curves
in dapsone-treated versus control animals.39 It is
taken orally once/day with or without meals,
with nearly complete absorption and peak serum
concentrations of 28 hours. There is no dosage

adjustment needed for patients with renal

dysfunction, but patients with hepatic impairment should be monitored closely. Dapsone may
cause hepatitis and cholestatic jaundice, but no
dosage adjustment guidelines are available for
those with liver disease.
Dapsone was initially used as monotherapy,
but resistance, estimated at 210%, has become
problematic.40 One proposed mechanism of
resistance is a mutant folP1 gene, which encodes
a resistant dihydropteroate synthase capable of
folic acid synthesis under a variety of extreme
conditions.41 In an effort to prevent the emergence of resistance expected with monotherapy,
multidrug therapy is the standard of care.
The adverse effects of dapsone can be quite
limiting with the most profound being methemoglobinemia and hemolysis related to glucose6-phosphate dehydrogenase (G6PD) deficiency.42
All patients should be screened for G6PD deficiency before starting dapsone, and those with
mild G6PD deficiency may be started at 25 mg/
day with close monitoring.35 Dapsone is used
in pregnant patients, although it is a category
C drug. It is excreted substantially in breast milk
and is potentially harmful to nursing infants with
G6PD deficiency. Cutaneous manifestations that
may be confused with worsening disease are also
possible, sometimes accompanied with lymphade-

TREATMENT OF HANSENS DISEASE Legendre et al

nopathy, fever, hepatitis, leukopenia, anemia, and
acute psychosis.43 There are also reports of
peripheral neuropathy, although this adverse
effect is rare.44
Rifampin
Although not U.S. Food and Drug Administration (FDA) approved for Hansens disease, rifampin is recommended for every manifestation of
the disease. It is rapidly bactericidal against M. leprae with bacteriologic success within 3 weeks of
starting therapy. Even a single high dose was efficacious in a mouse footpad model.45 The rifamycins bind to the b-subunit of RNA polymerase in
prokaryotic cells and block RNA transcription.
Bactericidal activity is observed even in slowly
dividing cells, such as Mycobacterium species.
Patients may take rifampin once/day unsupervised
or once/month supervised, depending on the treatment algorithm. It is readily absorbed with an elimination half-life of ~3 hours. It is available as an
intravenous infusion but is rarely used in this fashion for Hansens disease. There is no dosage
adjustment necessary for patients with hepatic
dysfunction, but the dose should be reduced by
50% when a patients creatinine clearance is less
than 10 ml/minute as calculated by the Cockcroft-Gault equation.36 Rifampin is a pregnancy
category C drug although not considered a teratogen, and the American Academy of Pediatrics considers rifampin compatible with breastfeeding
although it is excreted in breast milk.
Rifampin should never be used as monotherapy because of rapid development of resistance.
Point mutations in rpoB, which encodes the
b-subunit of RNA polymerase, are the likely
mechanism of resistance.46 Therefore, rifampin
is a component of multidrug therapy most commonly paired with dapsone, which reduces the
rate of clinical failure resulting from resistance
to either component.
Adverse effects of rifampin therapy include rash,
hepatotoxicity, and malaise. Patients should be
warned of orange discoloration of tears, urine,
and sweat, which can stain contact lenses and be
disconcerting to the patient. Mild thrombocytopenia is also possible, but this adverse effect
rarely requires discontinuation of the drug.
Rifampins rapidly bactericidal activity leads to a
proinflammatory state induced by subcellular
components of dead bacteria. Therefore, it is
contraindicated during the active phase of a
reversal reaction.35 The major issue with rifampin therapy is multiple drug interactions that

33

result from induction of the following cytochrome P450 isoforms: 3A4, 1A2, 2C8, 2C9,
2C19, and 2D6. Pharmacists should check for
drug interactions before starting therapy. Rifampin increases the metabolism of dapsone, but
this interaction is not significant for the treatment of Hansens disease. In contrast, the drug
interaction between rifampin and prednisone is
quite significant, and the rifampin dosage should
be reduced from 600 mg/day to 600 mg/month
with the addition of corticosteroid therapy.
Clofazimine
Clofazimine is a phenazine dye with antibacterial
activity similar to that of dapsone. Its mechanism
is poorly understood, but its ability to bind to
DNA of M. leprae may contribute to its antibacterial activity. There is also some suggestion that
the immunomodulatory activity of clofazimine
may be useful during reversal reaction. It retains
activity in the presence of dapsone resistance.47
Clofazimine is taken orally once/day, but it is
incompletely absorbed in the gastrointestinal
tract. Food may increase absorption. The adverse
effects are relatively mild, with gastrointestinal
symptoms and skin discoloration as the most
common. The skin discoloration manifests as
increased melanin pigmentation that persists after
therapy discontinuation, and there are reports of
suicide due to depression from this change. This
hyperpigmentation is also associated with sunlight sensitivity, so avoidance of prolonged sun
exposure is encouraged. As a dye, the drug can be
excreted in urine, sweat, and tears, so those wearing contact lenses should be cautioned.37
Clofazimine is no longer commercially available in the United States, but it can be obtained as
an investigational new drug through the NHDP.
The prescriber is considered to be an investigator
and must submit an FDA form 1572 and curriculum vitae to the NHDP. The institutional review
board is provided by the Centers for Disease Control and Prevention. Consent forms and other
documents will be provided to the prescriber
upon request. For more information, visit www.
hrsa.gov/hansens/clinical/regimens.htm or call
1-800-642-2477.
Fluoroquinolones
Although not considered primary therapy in
most instances, fluoroquinolones, such as moxifloxacin and ofloxacin, remain an important
option for treating Hansens disease, especially in

34

PHARMACOTHERAPY Volume 32, Number 1, 2012

patients with intolerance, resistance, or clinical

failure to primary therapy. Fluoroquinolones are
active against M. leprae by inhibiting DNA gyrase
and inhibiting DNA replication and transcription.48 Agents, such as moxifloxacin, exhibit powerful bactericidal activity similar to that of rifampin,
with one dose producing substantial kill. In one
study, no viable organisms remained after 3 weeks
of daily therapy.49 Ofloxacin has substantial activity
and is recommended as a single dose with
other drugs for single-lesion disease, but due to a
slightly increased failure rate compared with standard therapy, this regimen should be limited to
countries with limited resources or operational
difficulties.50, 51 Other agents in this class, such as
ciprofloxacin, show little to no activity.52 Fluoroquinolone resistance occurs primarily through mutations in gyrA but is not associated with mutations in
gyrB.53
Minocycline
Minocycline is the only tetracycline with intrinsic
activity against M. leprae. Minocycline is a lipophilic molecule that passively enters the bacterial
cells and exerts its action on the 30S ribosomal
subunit. Although not as active as rifampin, minocycline remains an effective and useful alternative
in the treatment of Hansens disease.54, 55 It is part
of single-lesion therapy recommended by the
WHO, and it has been used to successfully treat
patients with lepromatous leprosy at a dose of
100 mg/day.56 Adverse effects, even with longterm treatment, are usually very mild, although
skin pigmentation, gastrointestinal symptoms,
and central nervous system symptoms have been
reported. Minocycline should not be used in children or during pregnancy because it may deposit
in tooth enamel and discolor teeth.
Clarithromycin
Clarithromycin is a semisynthetic macrolide
antibiotic with bactericidal activity against M. leprae
greater than other macrolides although less bactericidal than minocycline.54 Its mechanism may be
due to reduction of ATP in the bacteria.57 It is useful as an alternative to primary therapy due to
either resistance or intolerance and has been used
to treat lepromatous leprosy as monotherapy
with success, although higher doses lead to some
gastrointestinal distress.58 Clarithromycin 500 mg/
day has been paired successfully with minocycline.56

Future Therapy
There is little in terms of novel therapy being
explored for future treatment of Hansens disease,
and the same is true for many diseases caused by
Mycobacterium species. The diarylquinolone,
R207910, is a promising new drug with bactericidal activity comparable to that of moxifloxacin
and rifapentine.59 Its novel mechanism is believed
to be inhibition of ATP synthase.60 In a murine
model, R207910 retained bactericidal capabilities
even when dosed once/month.61 Although it must
be studied in humans, this drug remains an exciting option for the future.
Prevention
Vaccines are effective at preventing infectious
diseases and epidemics. There is no vaccine for
M. leprae, but bacillus Calmette-Guerin (BCG),
often used as a tuberculosis vaccine, also offers
some protection against M. leprae, with a single
dose providing 50% protection. Some have advocated adding killed M. leprae to the BCG vaccine
for increased immunologic response, but trials
of this strategy conducted in Malawi have not
proved effective.62 Using BCG for prevention of
Hansens disease alone is not recommended at
this time, and BCG is generally not recommended for any indication in the United States.
Treatment of Immunologic Reactions
Immunologic reactions are medical emergencies that must be evaluated and treated
immediately to prevent long-term sequelae. Antimicrobial therapy should continue throughout
the type 1 (reversal) reaction, although many clinicians will stop rifampin, especially in the presence of active neuritis. Cutaneous manifestations
of a type 1 reaction generally do not require additional therapy. However, if the patient experiences loss of sensation or other peripheral nerve
symptoms, corticosteroids should be started
immediately to prevent permanent damage. Type
2 reactions may not respond to corticosteroids
alone, and the addition of drugs such as thalidomide may be useful in these cases. Patients not
responding to any therapy may benefit from clofazimine if not already taking this drug.
Corticosteroids
Corticosteroids provide symptomatic relief
from a reversal (type 1) reaction frequently within

TREATMENT OF HANSENS DISEASE Legendre et al

1 week. Prednisone 1 mg/kg up to 80 mg/day
tapered over several months can be used. The
dose may be increased by 20 mg/day if symptoms
persist after initiation of therapy. Prednisolone is
available as an oral solution that may be used in
place of prednisone. Long-term use of high-dose
corticosteroids certainly has complications associated with adrenocortical atrophy and hypoalbuminemia. Myopathy, osteoporosis, ocular effects,
hyperglycemia, and skin reactions are just a few
of the major adverse effects that must be monitored and addressed throughout the treatment.
Some practitioners will also prescribe a bisphosphonate, such as alendronate, to prevent
osteoporosis.
Thalidomide
The mechanism of action of thalidomide in
patients with Hansens disease is not fully understood, but it does reduce systemic concentrations
of TNF-a, a cytokine involved in systemic
inflammation. Thalidomide is useful for treatment for ENL when corticosteroids are not effective or are contraindicated. The initial dose is
100300 mg/day. Once symptoms subside, therapy can be tapered by 50 mg every 24 weeks.
Thalidomide is known to cause birth defects and
is a pregnancy category X drug. In this case, corticosteroids are the hallmark of therapy. Breastfeeding is also contraindicated while taking
thalidomide. Those who wish to prescribe therapy must be licensed through the System for
Thalidomide Education and Prescribing Safety
(STEPS) program, and pharmacists are also
responsible for complying with these regulations.
Pentoxiphylline
This methylxanthines mechanism of action is
unknown, but oral pentoxiphylline 400800 mg 3
times/day appears to decrease levels of TNF-a.63
The major adverse effects are related to the
gastrointestinal tract and central nervous system, but these effects are reduced by using
a controlled-release formulation. Thalidomide
outperformed pentoxiphylline in a randomized
clinical trial in patients with type 2 reactions,
in terms of limb edema and systemic symptoms, but 62.5% of patients in the pentoxiphylline group had symptom relief. Although
this drug is not first line, it is a useful option
when other therapies are ineffective or contraindicated.64

35

Tumor Necrosis Factor Inhibitors

Since the mechanism of action of several drugs
is proposed to inhibit TNF-a concentrations,
biologic TNF inhibitors are a promising option
for treatment of refractory type 2 reactions.
Various case reports show successful treatment of
difficult reactions with etanercept and infliximab.65, 66 However, these drugs are known to
exacerbate infectious complications, and several
case reports show development or worsening of
disease with agents such as infliximab and adalimumab.67, 68 It is interesting to note that two
patients who developed disease when starting infliximab also developed a type 1 reaction after its
discontinuation. The true efficacy and safety of
these drugs in type 2 reactions are still unknown,
but these drugs may be useful in situations when
all other therapies are ineffective and the patient
desperately needs relief of symptoms.
T Cell Inhibitors
There is some evidence that drugs that disrupt
T cell activation and function can provide relief
during a reaction. Oral cyclosporine resulted in
complete response in 3 of 4 patients, with the
remaining patient achieving a partial response.69,
70
However, M. leprae grew more readily in
BALB/c mice infected with M. leprae who were
treated with extended courses of cyclosporine.71
Sixty-seven patients, with 20 experiencing
chronic neuritis while receiving prednisone,
were treated with cyclosporine 5 mg/kg reduced
over 12 months.72 Therapy resulted in reductions of antibodies to nerve growth factor to
normal levels and improvement of sensory
impairment. One published case reported
dramatic improvement of skin lesions after
daily topical administration with tacrolimus
0.1%.73 Cyclosporine and other drugs that inhibit T cells are another option for patients not
responding to standard treatment of a reaction.
Adjunctive Therapy
There is little evidence that directly supports
the use of nonsteroidal antiinflammatory drugs,
but they are commonly used in very high doses to
treat reactions, because of their antiinflammatory
effects. Amitriptyline and gabapentin have also
been used to mitigate neuropathy despite little
evidence to demonstrate effect. Some evidence
points to the utility of leukotriene inhibitors,
such as zafirlukast, in the treatment of ENL.74

36

PHARMACOTHERAPY Volume 32, Number 1, 2012

The Leprosy Mission in Bangladesh proposed a

clinical study in 2006 to test montelukast. In Bangladesh, thalidomide is unavailable and clofazimine is difficult to obtain. However, no patients
have been enrolled in this trial to date.
Conclusion
Hansens disease (leprosy) remains problematic in the United States and throughout the
world. Transmission of bacteria from person to
person is uncommon, and armadillos remain the
major reservoir in the United States. There is no
efficient way to grow the organism in culture,
which makes research efforts difficult. Prompt
recognition of disease and treatment reduces
disease signs and symptoms, such as anesthetic
lesions, loss of vision, and amputation. The
discovery of antibacterial therapy targeting
M. leprae has dramatically improved those
infected with Hansens bacillus. Patients benefit
from comprehensive care involving numerous
health care professionals. Astute pharmacists
who effectively manage antibacterial and reaction therapy will notice improved patient outcomes and quality of life. Major complications
today involve immunologic reactions and drug
resistance due to lack of compliance. Clinicians
can recognize these issues early and adjust treatment appropriately to limit long-term complications from this disease.
Acknowledgments
The authors would like to thank Barbara Stryjewska, M.D., and Jackie Lea, R.Ph., from the NHDP
for helpful discussions regarding the manuscript.

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