Recent advances in the treatment of leprosy
Norihisa Ishii, MD, PhD
Dermatology Online Journal 9 (2): 5

Director, Department of Bioregulation, Leprosy Research Center, National Institute of Infectious Diseases, Higashimurayama, Tokyo, JAPAN, norishii@nih.go.jp

Abstract

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, was identified by G. H. A. Hansen in 1873. The different clinical presentations of the disease are determined by the quality of the host immune response. The bacteria have affinity for the peripheral nerves and are likely the cause of neuropathy, a cardinal manifestation of the disease. WHO recommends a protocol of multidrug therapy (MDT), which effectively controls the disease, hence contributing to the global elimination program. Early detection of leprosy and treatment by MDT are the most important steps in preventing deformity and disability.


Abbreviations
  • B group: borderline group
  • BI: bacterial index
  • CAM: clarithromycin
  • CLF: clofazimine
  • Dapsone: diaphenylsulfone (DDS)
  • ENL: erythema nodosum leprosum
  • G6PD: glucose 6 phosphate dehydrogenase
  • I group: indeterminate group
  • LL type: lepromatous type
  • LVFX: levofloxacin
  • MINO: minocycline
  • M. leprae Mycobacterium leprae
  • MB: multibacillary
  • MDT: multidrug therapy
  • OFLX: ofloxacin
  • PB: paucibacillary
  • RFP: refampicin
  • SLL: single lesion leprosy
  • SPFX: sparfloxacin
  • TT type: tuberculoid type
  • WHO: world health organization


Introduction

Leprosy, also known as Hansen's disease, is a chronic infectious disease that primarily affects the skin, the peripheral nerves, the upper respiratory tract, and the eyes.[1] The causative agent is an acid-fast bacterium, Mycobacterium leprae, first identified in 1873 by the Norwegian physician, Gerhard Henrik Armauer Hansen.

Leprosy was considered a divine curse for sin in the Old Testament and a karma in Buddhism. The term leprosy originates from the Latin word lepros, meaning defilement. The fact that leprosy has been deemed an incurable disease, causing severe deformities and disabilities, has resulted in severe stigmatization. This has resulted in double suffering by victims, both from the disease itself and from public discrimination. Although documented since antiquity, leprosy currently remains endemic in some developing parts of the world.[2]

In 1991, the World Health Organization (WHO) and its member states committed themselves to eliminate leprosy as a public health problem by the year 2000.[3] Elimination was defined as a prevalence of less than 1 case per 10,000 persons. At the end of the year 2000, the deadline of the program, 597,232 leprosy cases were registered for treatment and 719,330 cases were newly detected in the world.[4] The prevalence rate at the global level was below 1 case per 10,000 persons. Out of the 122 considered endemic in 1985, 107 countries have reached the elimination goal. There have been 690,830 newly detected patients in 2001, 91% of cases detected worldwide live in the top six countries where the disease is most prevalent and endemic (Table 1). The prevalence rate in these top 6 countries has been estimated at 3.9 per 10,000, with a very uneven distribution (Table 1). India accounts for 78% of the cases, and its elimination program is of major importance for global leprosy control.

Table 1
Prevalence and detection rate of leprosy in the top 6 countries where the disease is endemic
Country Prevalence cases
1-Jan-02
Prevalence rate
per 10,000
Cases detected
in 2001
Detection rate
per 100,000
India 439,782 4.3 617,993 60.1
Brazil 77,676 4.5 41,070 23.8
Nepal 10,657 4.4 13,830 56.5
Mozambique 6,775 3.4 5,713 28.5
Angola 4,115 3.1 2,540 19.1
Myanmar 8,237 1.8 9,684 21
Total(World) 635,404 1 763,315 12.3


Major target of leprosy control

Leprosy, which was endemic in Western Europe in the medieval period, was eliminated from Scandinavian countries only as recently as the early twentieth century, before the advent of antibiotic therapy. Obviously, this decline must be attributed to improvement in living standards, better housing, clean water supplies, and improved nutrition and hygiene. Currently, very few newly registered patients are found in developed countries and, when detected, a significant proportion of them are immigrants from countries where the disease is still endemic. Today, leprosy is found mainly in developing countries, around the subtropical and tropical zone, where the social and economic resources have not been sufficient to support the living standards needed to limit the disease. Current protocols for the diagnosis and treatment of leprosy have been adapted to correspond to the medical standards of developing countries. In this review article, we intend to introduce the protocol for leprosy treatment that was standardized by WHO. (see http://www.who.int/lep/).


Diagnosis and classification of leprosy

The diagnosis of leprosy is mainly based on the clinical signs and the symptoms of the disease. Most leprosy health workers, with the required, generally short training, can easily observe and recognize these features, although in general, persons with specific complaints would report on their own to the health center. Only in rare instances, there is a need for laboratory and other investigations for diagnosis confirmation.

In an endemic country or area, the following cardinal signs should make an individual suspect for leprosy:

  • skin lesion consistent with leprosy and with definite sensory loss, with or without thickened nerves
  • positive skin smears

The classification of leprosy is based upon 2 basic criteria that are, the clinical manifestations and the results of skin smears. In the classification based on skin smears, patients showing negative smears at all sites are grouped as paucibacillary leprosy (PB), while those showing positive smears at any site are grouped as having multibacillary leprosy (MB). However, skin smear services are not generally available. This made it more practical for most programs to use clinical criteria for classifying and determining the appropriate treatment regimen for individual patients. The clinical classification, for the purpose of treatment, uses the number of skin lesions and nerves involved as the basis for grouping leprosy patients into PB and MB leprosy (Figure 1). In this system, one skin lesion, is designated single (skin) lesion of PB (SLPB). In case of doubt, the patient should be included in MB leprosy. PB and MB classification is useful to differentiate the two forms and to determine the treatment regimen.

While classifying leprosy, care should be taken to ensure that patients with one form of the disease are not treated with the regimen of the other form. In case of diagnosis uncertainty, the MDT regimen is advisable. The Ridley-Jopling classification, based upon immunological status of patients to M.Leprae[5], is divided into 2 groups (I group and B group) and 2 types (TT type and LL type). The latter classification is somehow laborious in the identification of patients by both health workers and Dermatologists.


Laboratory Test

A primary skin smear would be the ideal prerequisite before the start of a treatment regimen, in cases where reliable laboratory facilities are available. This would ensure that an MB case is not treated as a PB one. When a treatment regimen's durations are set, skin smears are no longer needed either for the termination of the treatment or as a tool for surveillance in the follow-up of patients. Suspicion of clinical deterioration and/or relapse should indicate the use of skin smears at the most active sites. However, restraint should be exercised regarding the number of skin-smear sites and the frequency of smear collection. The prevalence of human immunodeficiency viruses (HIV) and hepatitis B infections in many countries where leprosy remains endemic dictates the need for caution in handling such specimens.


Treatment principles for leprosy

The major goals of the leprosy control program are (1) early detection of patients; (2) appropriate treatment; and (3) adequate care for the prevention of disabilities and rehabilitation. Because leprosy is an infectious disease, antibiotic therapy plays a pivotal role in the management of newly diagnosed patients.

There are several effective chemotherapeutic agents against M. leprae. Dapsone (diaphenylsulfone, DDS), rifampicin (RFP), clofazimine (CLF, B663), ofloxacin (OFLX), and minocycline (MINO) constitute the backbone of the multidrug therapy (MDT) regimen recommended by WHO. Other chemotherapeutic agents, like Levofloxacin (LVFX), sparfloxacin (SPFX), and clarithromycin (CAM) are also effective against M. leprae [6, 7, 8]. WHO has designed very practical kits containing medication for 28 days, dispensed in blister packs, for both PB and MB leprosy. The blister pack medication kit for SLPB leprosy contains the exact dose for the one-time administration of the three components of the MDT regimen.

Following the classification according to the flowchart (see Figure 1), PB patients receive 600 mg RFP monthly, supervised, and 100 mg dapsone daily, unsupervised, for 6 months. SLPB patients can be treated with a single therapeutic dose consisting of 600 mg RFP, 400 mg OFLX, and 100 mg MINO. MB cases are treated with 600 mg RFP and 300 mg CLF monthly, supervised, and 100 mg dapsone and 50 mg CLF daily, for 12 months. Reduced doses of the above regimen are appropriately determined for children [9, 10, 11, 12, 13].

Directly, monthly supervised treatment of RFP is very important to avoid drug resistance. An additional 27 days of treatment with dapsone (and CLF) are mandatory and, health workers should ensure that regular and daily, uninterrupted drug intake is performed.


Treatment: multidrug therapy (MDT)


MDT is a key element of the leprosy treatment and elimination strategy. For both PB and MB leprosy, RFP is central to the antileprosy drug regimen (Table 2). It has been proven that monotherapy in leprosy will result in the development of resistance to the drug used. Thus, monotherapy with dapsone or any other antileprosy drug should be considered unethical practice. Tables 3 and 4, respectively, show the pharmacological effects of each drug and the recommended laboratory monitoring.

Table 2A
Multidrug Therapy for Multibacillary (MB) Leprosy

PFP Dapsone CLF
Adult
50-70kg
600mg/m* 100mg/d 50mg/d &
300mg/m*
Child
10-14 years
450mg/m* 50mg/d 50mg/d &
150mg/m*
Less than 10 300mg/m* 25mg/d 50mg twice/w &
100mg/m*
*PFP and CLF monthly doses are given under supervision

Table 2B
Multidrug Therapy for Paucibacillary (PB) Leprosy

PFP Dapsone
Adult
50-70kg
600mg/m* 100mg/d
Child
10-14 years
450mg/m* 50mg/d
Less than 10 300mg/m* 25mg/d
*PFP and CLF monthly doses are given under supervision

Table 2C
Multidrug Therapy for
Single Lesion Paucibacillary (SLPB) Leprosy

PFP OFLX MNO
Adult
50-70kg
600mg 400mg 100mg
Child
5-14 years
300mg 200mg 50mg
Not recommended for pregnant women
and children less than 5 years old

Table 3
Pharmacological effect of drugs applied for Leprosy
RFP    bactericidal
Dapsone   bacteriostatic, weakly bactericidal
CLF    slow bactericidal
OFLX    bactericidal
MINO    bacteriostatic
SPFX    bactericidal
CAM    bacteriostatic, weakly bactericidal

Table 4
Laboratory monitoring for drugs used to treat leprosy
Drug Laboratory studies frequency
Initial studies
for all drugs
CBC, platelets, UA, Chemistry Baseline
DDS G6PD, CBC every 6 months
RFP CBC, platelets, Chemistry every 3 months
CLF no recommended lab. studies
Thalidomide CBC every 2 months

Rifampicin (RFP): The drug is administered in a single monthly dose, a protocol for which no significant toxic effect has been reported. Exceptionally bactericidal against M. leprae, a single dose of 600 mg of RFP is capable of killing 99.9% or more of viable organisms. However, the rate of killing is not proportionately enhanced by subsequent doses. It has been suggested that RFP may exert a delayed antibiotic effect for several days, during which the organism's multiplication is inhibited. The high bactericidal activity of RFP made feasible the application of the single monthly dose, which is cost-effective for leprosy-control programs. At the start of the treatment, the patient should be informed of the usual side effect of a slight reddish coloration of urine.

Diaminodiphenylsulfone (DDS, dapsone): Until widespread resistant strains to the drug were reported, dapsone, which is bacteriostatic or weakly bactericidal against M. leprae, was for years the mainstay in the treatment regimen for leprosy.[14, 15] Subsequently, its use in combination with other drugs has become essential to slow or prevent the development of resistance. The drug has demonstrated an acceptable level of safety in the dosage used in MDT. Besides occasional cutaneous eruptions, side effects that necessitate discontinuation are rare. Patients known to be allergic to any of the sulpha drugs should be spared dapsone. Anemia, hemolysis, and methemoglobinemia may develop but are more significant in patients deficient for glucose-6-phosphodihydrogenase (G6PD).

Clofazimine (CLF): CLF, which preferentially binds to mycobacterial DNA, both inhibits mycobacterial growth and exerts a slow bactericidal effect on M. leprae.[16, 17] Anti-inflammatory properties have been suggested, for the drug controls erythema nodosum leprosum reactions by mechanisms still poorly understood. Most active when administered daily, the dosage used for MDT is well tolerated and has not shown significant toxicity. Because CLF is a repository drug, stored in the body after administration and slowly excreted, it is given as a loading dose of 300 mg once a month to ensure that the optimal amount of CLF is maintained in the body tissue, even if patients occasionally miss their daily dose. Patients starting the MDT regimen for MB leprosy should be informed of side effects including brownish black discoloration and dryness of skin. These usually disappear within a few months of treatment suspension.

Recently three more drugs have shown bactericidal activity against M. leprae. These are ofloxacin (OFLX) -a fluoroquinolone, minocycline (MINO) -a tetracycline, and clarithromycin-a macrolide.

Ofloxacin (OFLX) : OFLX, a synthetic fluoroquinolone, acts as a specific inhibitor of bacterial DNA gyrase and has shown efficiency in the treatment of M. leprae.[18] Chromosome resistance of negligible clinical relevance has been reported.

Minocycline (Minocycline (MINO) is a semisynthetic tetracycline. [19] It achieves selective concentration in susceptible organisms and induces bacteriostasis by inhibiting protein synthesis.

However, from the curative and cost-effectiveness points of view, the WHO-recommended, time-honored MDT remains to date the best combination regimen of the worldwide leprosy-control programs.


Treatment of PB leprosy

In PB patients, it is assumed that 6 months of treatment with RFP alone can ensure a complete clearing of the bacteria. However, to prevent RFP resistance dapsone has been added. The attainment of clinical inactivity should not be the condition guiding the continuation of MDT in PB patients, because these patients are virtually always cleared of viable bacteria in 6 months with the WHO-MDT regimen. Hence, one should keep in mind that clinical activity in PB leprosy does not necessarily directly correlate with bacterial multiplication. In a substantial proportion of patients, clinical inactivity may not be achieved in 6 months even after a complete clearing of the organisms. Follow-up studies of PB patients in MDT's field trials have shown that complete clearing of lesions takes 1–2 years after treatment discontinuation. The incidence of relapses in PB patients is very low, and, to date, the correlation between disease activity status at the time of treatment completion and subsequent relapse is not well documented. Nevertheless, the accuracy of the initial classification of patients in the PB category is a determining factor of long-term results.


Treatment of SLPB

In 1997, WHO initiated the supply of special ROM(R: rimfanpicin. O: Ofloxacin. M: minocycline) blister packs to India, Bangladesh, Nepal, and Brazil for the treatment of SLPB leprosy. The 7th WHO expert committee on leprosy recommended the use of a combination of RFP 600 mg, OFLX 400 mg and MINO 100 mg (ROM) for the treatment of two categories of leprosy patients. Patients presenting with SLPB leprosy could be treated with a single dose of ROM. Both experimental and clinical studies have shown the bactericidal effectiveness of these drugs, either alone or in combination. Therefore, for the treatment of SLPB leprosy, WHO advocates a flexible attitude to the decision of whether to use a single dose ROM or the standard WHO-MDT for 6 months.


Treatment of MB leprosy

RFP remains the major component of the MDT regimens, clearing most RFP-susceptible strains of M. leprae with a few monthly doses. Recently it has been shown that the daily combination of dapsone and CLF is highly bactericidal. The combination has been very effective on RFP-resistant mutants in an untreated MB leprosy patient within 3–6 months. For the treatment of MB leprosy, controlled and reliable clinical trials have demonstrated that MDT is generally effective within 24 months or less. Such observations led WHO to recommend 12 months as an acceptable duration for the MDT regimen in the efficient treatment of MB leprosy.

Some concerns arose regarding this 12-month regimen for the treatment of high bacteriological index patients. Observations have shown that a high bacteriological index in MB patients correlates with a high risk for the development of adverse reactions and nerve damage during the second year of treatment. Also, a high bacteriological index at the start of the treatment regimen has been correlated not only with a slow disappearance of skin lesions but also with a high index at the end of the 12-month regimen compared with patients starting with a lower bacteriological index. However, it was found that most of the high bacteriological index patients will continue to improve after the completion of the 12-month regimen. Nevertheless, an additional 12 months of MDT for MB leprosy is needed for patients showing evidence of deterioration.

Provided there is a strict adherence to the regimen by the patient, the shortening of the MDT for MB leprosy from 24 months to 12 months will not lead to a higher risk for the development of resistance to RFP. Several studies have demonstrated that a few doses of RFP are able to clear all the organisms susceptible to RFP. The naturally occurring RFP-resistant mutants are very sensitive to the CLF-dapsone combination, leaving very little chance for any bacteria to survive 12 doses of MDT.

The prevalence of MB patients with a high bacterial index is decreasing in most programs. WHO has estimated their proportion among newly detected cases to less than 15%. There is evidence that 3–6 months of administration of MDT clears all live organisms. Also, for reasons of nonavailability or nonreliability of skin smear services, increasing numbers of leprosy control programs are classifying leprosy patients on clinical criteria alone. A factor of supreme importance in the surveillance of the treatment is the determination by the control program of patients with high bacteriological index and those with high risk of developing reaction and neuritis. This surveillance should be done by both clinical and bacteriological methods. Such selected patients may be kept on surveillance for 1–2 years in order to detect deterioration and adverse reactions as early as possible. Signs of deterioration are an indication of the necessity of an additional course of 12 months of MDT. In general, reactions are successfully managed by a standard course of prednisolone. A key element of the surveillance is the education of patients at the end of the treatment program. The benefit of the treatment program would be seriously undermined if the patients were to ignore the symptoms and signs of relapses, and not report them at their slightest manifestation. MB leprosy patients who do not accept CLF can be treated with the monthly administration of 24 doses of ROM.


MDT and M. leprae

Persisting M. leprae are defined as viable organisms which are fully susceptible to the drugs but survive despite adequate treatment with antileprosy drugs, probably because they are in a low or dormant metabolic state. To the best of our knowledge, drugs that can clear these persisting organisms are as yet undetermined, although RFP is known for its capability to kill persisting organisms in another mycobacterial disease, tuberculosis. Evidence so far accumulated has shown that persisting organisms, even though present, do not play a key role in the occurrence of relapses in leprosy among patients treated with MDT.

In most patients, the presence of dead bacilli in the skin and other tissues seems to be pathogenically insignificant and the dead organisms are gradually cleared away by the body's phagocytic system. The results of several large-scale, long-term field trials show that the rate of clearance of dead bacilli is about 0.6–1.0 logs per year and is not enhanced by MDT. However, in a very small proportion of patients, antigens from dead bacilli can provoke immunological reactions, such as the (late) reversal reaction, causing serious nerve damage and subsequent disabilities. Patients should be aware of this potential advent. These reactions are effectively managed by corticosteroids such as prednisolone.

Although the risk of possible endogenous reactivation is negligible when adequate chemotherapy has been completed, evidence exist for other mycobacterioses, like tuberculosis, that immunosuppressive drugs, like prednisolone, can accelerate the multiplication of organisms in a dormant state and cause a disseminated reactivation. Nothing of the like has been documented in leprosy. In case steroid therapy is expected to exceed 4 months, prophylactic measures should be considered. Daily administration of 50 mg of CLF has been used in these cases and should be continued throughout the course of steroid therapy. However, these patients should not be reentered into the case registry.


MDT and drug-resistance

Resistance of M.Leprae to existing major anti-leprosy drugs has been world wide reported. It has become imperative to develop parades to overcome this problem, the magnitude of which was selective. Actually resistance to Dapsone was the most reported. Subsequently regimens of the MDT were designed on the principle that they would be effective against all the strains of M. leprae regardless of their susceptibility to dapsone.

Reports on RFP-resistant leprosy came second to those of Dapsone in term of frequency. Currently, the problem of RFP-resistant leprosy is trivial; however, selective non-compliance with dapsone and/or CLF by patients may facilitate the selection of RFP-resistant strains. This resistance to RFP is believed to develop as a result of its use in monotherapy or in combination with dapsone, to dapsone-resistant patients.

It has been estimated that an advanced, untreated MB patient harbors about 11 logs live organisms. Out of these, the proportion of naturally-occurring drug-resistant mutants is estimated to be 1 in 7 logs for RFP; 1 in 6 logs each for dapsone and CLF. The organisms resistant to one drug will be susceptible to the other drugs in MDT as their mechanisms of action are different. To date, reports of relapses after treatment with MDT have been rare. Their management with the same regimen has been equally effective.

All experimental and clinical facts indicate that there is no antagonism among the drugs comprising MDT. The experience with MDT so far has shown the combination to be the most effective one. Recently, genetic profiles of drug-resistant strains have been elucidated (Table 5).

Table 5
Mycobacterium leprae-resistant gene
Drug gene Function of gene
  RFP rpoB DNA dependent-RNA polymerase β subunit
  DDS folP dihydropteroate synthesis
  CLF   ?   ?
  OFLX gyrA DNA gyrase


Leprosy reaction and its treatment

Leprosy affects all aspects of patients' life (Reviewed in [24]). Its reactions, known under the label "Leprosy reactions" include among their worst consequences, irreversible nerve damage and disabilities. Fortunately, these reactions have become gradually well documented and, if timely detected, they are eventually preventable. They occur in all PB and MB (B group and LL type) patients, most commonly during chemotherapy. PB and MB (B group) cases develop type 1 reaction (reverse reaction: RR), and type 2 reaction (erythema nodosum leprosum: ENL) occurs in MB (LL type) patients [13, 33]. Some data seem to indicate a trend toward a reduction in the frequency and severity of ENL in MB leprosy patients on MDT. These data may be attributable to the anti-inflammatory effect of CLF. [21, 22] On the other hand, a temporary increase in the reporting of reversal reactions (type 1) has been noted in MB leprosy patients in their first year of MDT. The exact meaning of this observation remains unclear. One of the most likely explanation is the improvement of early and specific detection capability. Usually these reactions respond satisfactorily to predonisolone, [13, 23] along with thalidomide or CLF (Table 6).[24] In the case of permanent impairment, methods for rehabilitation must be addressed.

Table 6
Treatment of Lepra Reaction
Reaction Prednisolone CLF Thalidomide
Reversal
reaction
(type 1)
up to 1 mg/kg/d
then gradually reduced
   
ENL
(type 2)
up to 1 mg/kg/d
then gradually reduced
up to 300 mg up to 400 mg
Maximum daily dose is shown when single use
Combination therapy is recommended in ENL
Thalidomide should be avoided in women of childbearing age


Relapse of leprosy

Evaluating the effectiveness of a chemotherapeutic regimen is essential to the leprosy-control program. One of the best methods of evaluation is the monitoring of relapse after the completion of a respected treatment protocol. [25, 26, 27, 28, 29, 30] Data gathered by the Action Programme for the Elimination of Leprosy, WHO, from a number of control programs show that the relapse rate is very low (0.1% per year for PB and 0.06% per year for MB on the average). The program seems to be accepted worldwide. A likely explanation of this trend is probably the low frequency of side effects.

For MB patients, WHO has set 12 months or more of MDT as acceptable criteria for a sustainable cure and removal from registries. Special mention has been granted to education. In this regard, a first emphasis has been put on the vital necessity for patients to know the signs and symptoms of reactions and relapses. Equally important is the obligation for an immediate reporting of the earliest manifestation of these signs to the relevant health centers. Improvements in the control program are such that it is no longer necessary to continue active surveillance after MDT programs. What remains mandatory as mentioned above is the reporting of any new lesions to the program even after a single dose of MDT.


Prolonged treatment

Overzealous or emotional attitudes should be avoided. Hence, reasons such as compliance with concerned patients' wishes or possible doubt about the effectiveness of the regimen as designed by WHO may bring some to feel the need to continue with dapsone monotherapy after a regular course of MDT. Such an attitude should be discouraged. Some reports have suggested a strong correlation between several years of dapsone monotherapy and a high frequency of relapse, especially in MB leprosy patients. For this reason, WHO's MDT for 12 months is highly recommended. There is no doubt that pertinent aspects of the pathophysiology of leprosy are not yet completely understood, but attitudes and guidelines codified for the management of this disease are generally the result of carefully controlled studies by a devoted community of competent clinicians, scientists and leprosy workers. A strong recommendation is then to respect these now worldwide-accepted guidelines.


Side effects of drugs

One of the risks of combination therapy is probably the collective side effects. Fortunately, side effects reported worldwide after the use of MDT in thousands of patients remain mild and rare. However, the attribution of the adverse reactions to the individual constituents of the MDT should be clearly and unequivocally established. Such an attitude will lay the way for the use of new antileprosy drugs. Among the troublesome side effects is the common brown-black skin discoloration induced by CLF. Its appearance starts around the third month. An observable decrease is noticed beginning around 6 months after stopping the regimen and usually by 12 months the skin has returned to its normal pigmentation. In dry climatic settings, trivial annoyances like xerosis may accompany such discoloration. Xerosis can be easily managed by the use of moisturizers. Reducing exposure to sunlight is also advised.

Dapsone occasionally causes severe systemic, cutaneous, or hematological hypersensitivity or toxic effects. In some PB patients it has been successfully substituted with CLF in a dosage similar to that used for MB patients for 6 months. When dapsone must be stopped, treatment may be continued in MB patients with RFP and CLF in the standard dosage.

RFP may be replaced by a daily regimen of 400 mg of OFLX and 100 mg of MINO in association with the daily administration of 50 mg of CLF for the first semester. This regimen is to be followed by daily administration of 50 mg of CLF, 400 mg of OFLX or 100 mg of MINO for the next 18 months. This regimen requires direct supervision in a referral center.


MDT and medication irregularity

Irregularity in administration of medication can cause serious harm to the MDT program. Not only may the patient become a source of contamination, but also the consequences may range from delayed and incomplete cure to the progression of the disease's activity and the development of disabilities and deformities. Concerns about the development of multidrug resistance must be taken seriously. It should be a matter of serious concern if a PB patient after 9 months has not completed the 6-month course of MDT. Equally dangerous would be a situation in which an MB patient after 18 months had not completed 12 months of the MDT course. Whenever possible, efforts should not be spared to bring back patients with lax discipline for adequate assessment and treatment. Such a defaulter, on returning to the health center for treatment, should be given a new course of MDT if he shows one or more of the following signs:(1) reddish or elevated skin lesions; (2) new skin lesions since last examination; (3) new nerve involvement since last examination; (4) lepromatous nodules; and (5) signs of ENL or reversal reaction.


MDT and HIV, Pregnancy, and TB

Existing data has shown that the response to MDT by leprosy patients infected with HIV has been similar to that of all other leprosy patients.[31] Hence, HIV infection in leprosy patients is not a contraindication for MDT. Leprosy management remains the same as in non-HIV-infected leprosy patients.

It is established that pregnancy exacerbates leprosy. Fortunately, MDT during pregnancy appears to be safe; no contraindications have been established currently.[32] CLF is excreted through breast milk and can cause mild discoloration of the infant.

MDT is not contraindicated in patients suffering from tuberculosis. However, because WHO's MDT for leprosy is not the ideal treatment for tuberculosis, an appropriate antitubercular regimen should be added to the antileprosy MDT in patients in whom the two diagnoses are confirmed. If daily RFP is part of the antituberculosis treatment, there is no need to administer monthly RFP as part of the leprosy MDT.


Failure of the MDT: lack of clinical and bacteriological improvement

A total lack of clinical and bacteriological clearing can occur in a small number of patients under MDT. Poor drug compliance and debilitating, recurrent infections seem the most likely explanation for such unresponsiveness. Poor compliance with medicine administration would generally be solved by supervised drug administration and health education, but recurrent infection needs thorough investigation (including, when indicated, tests for HIV infection) and appropriate management.


Vaccination

Vaccination against the leprosy bacillus may be considered. BCG vaccination is reported to be partially effective for protection against leprosy. [33, 34] However, a worldwide BCG vaccination program against M. leprae is not economically feasible; a cost-effective DNA vaccine could become a promising substitute.[23] Currently, vaccination against leprosy is not available, leaving MDT the only adequate weapon against M. leprae in the global leprosy-control program. The recent, considerable progress in molecular engineering has allowed the elucidation of the entire sequence of the M. leprae genome ( Table 7 ).[35] New vaccine strategies will probably develop, using these genomic sequence techniques.

Table 7
Comparison of genome features
Feature M.leprae M.tuberculosis
Genome size (bp) 3,268,203 4,411,532
G+C (%) 57.79 65.61
Protein coding (%) 49.5 90.8
Protein-coding genes (no.) 1,604 3,959
Pseudogenes (no.) 1,116 6
Gene density (bp per gene) 2,037 1,114
Average gene length (bp) 1,011 1,012
Average unknown gene length (bp) 338 653
(Nature 409:1007-11, 2001)


Deformity, disability and rehabilitation

Leprosy results in a wide range of impairments, the most debilitating being the damage to peripheral nerves. Damage to peripheral nerves causes regional loss of sensory, motor, and autonomic nerve function with subsequent deformity, resulting from repeated trauma of the skin. These consequences of nerve damage have an impact on the quality of life of those affected by the disease and also generate stigma. Prevention of nerve damage and the management of impairments are important components of any leprosy program. Leprosy rehabilitation should be fully integrated within existing community-based rehabilitation programs on an equal basis as those with disabilities due to other causes.

Acknowledgment: I am grateful to Prof. Milanga Mwanatambwe for critical comments.

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Title:

Recent advances in the treatment of leprosy

Journal Issue:

Dermatology Online Journal, 9(2)

Author:

Ishii, Norihisa MD PhD

Publication Date:

2003

Publication Info:

Dermatology Online Journal, UC Davis

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