Mycobacterium leprae

Authors: Carlos Franco-Paredes, M.D.

Authors, 1st Edition: Christian Lienhardt, MD, DTM, MSc, Keith P.W.J. McAdam, MA, MBBChair, FRCP, FWACP

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History

Leprosy is a chronic bacterial infectious disease caused by Mycobacterium leprae (19). This infection targets skin, peripheral nerves, and the eyes (5, 32). The mucosa of the upper respiratory tract, muscle, bones, and testes may also become involved during the course of this infection, particularly during the occurrence of a type 2 reaction or Erythema Nodosum Leprosum (ENL) (11). Rarely, a rare clinical form termed diffuse Lucio’s leprosy may produce a severe systemic necrotizing vasculopathy (59).

Approximately, only five percent of the world’s population is susceptible to infection and disease caused by M. leprae. This bacterial pathogen has a tropism to infect keratinocytes and histiocytes on the skin, and Schwann cells (40). The histopathologic and pathogenesis of leprosy is perineural inflammation and granuloma formation (44). Once M. leprae enters into Schwann cells, it leads to axonal dysfunction and atrophy; and segmental demyelination. Inside Schwann cell, M. leprae may also favor its systemic spread by inducing a process of dedifferentiation into stem cells that may carry the leprosy bacillus through other organs (40). Due to the fact that close contacts to a case become new cases, the mode of transmission is believed to occur from person to person via respiratory droplets (50).

The natural history of leprosy is characterized by two distinct pathogenic processes (44, 59): 1) a peripheral neuropathy produced by the perineural inflammation causing nerve injury (29); and 2) uncontrolled immune responses targeting peripheral nerves which can further exacerbate nerve damage. Leprosy can be diagnosed clinically by identifying characteristic skin lesions with anesthesia or hypoesthesia and palpating thickened peripheral nerves. The presence of granulomatous inflammation in skin and nerve biopsy specimens or acid-fast bacilli in slit skin smears confirms this infection. Without treatment, nerve damage can continue and become profound. Leprosy is associated with severe disability and dysfunction associated with peripheral nerve dysfunction. The range of clinical phenotypes has been defined by several classification systems, based primarily on histopathologic findings, immunological patterns, and prevalence of bacilli on biopsy (44, 56).

MICROBIOLOGY

M. leprae is a straight rod shaped bacillus 1-8 m long and 0.3 m diameter. Its capsule is composed of two lipids, phthiocerol dimycoserosate and a phenolic glycolipid, chemically unique and antigenically specific to M. leprae (9). The cell wall is composed of two layers: the outer layer contains lipopolysaccharide and the inner layer peptidoglycan. Under the cell wall, there is a membrane composed of lipids and proteins. The cytoplasm contains storage granules, DNA and ribosomes. M. leprae is an obligate intra-cellular parasite in man, multiplying mainly in histiocytes and Schwann cells. The entry of the bacilli into the Schwann cells causes peripheral neuropathy. The role of a cell wall phenolic glycolipid (PGL-1) in this invasion has been described (35).

Elucidation of its genome sequence has been a major undertaking (6). The most striking finding is the difference observed between M. leprae and its pathogenic relative, M.tuberculosis: instead of the tightly packed 4000-gene chromosome of M. tuberculosis, the M. leprae sequence encodes only 1600 predicted open-reading frames, with half of the genome taken up by scrambled pseudogenes. The information deduced from the genome sequence provides clear explanations for the mechanisms of drug action and resistance and opens new avenues for the development of new compunds.

EPIDEMIOLOGY

Humans are the only commonly accepted reservoir, although natural infection has been documented in armadillos in in North America, and in some primates in Africa (54, 55). The incubation period ranges from 9 months to 20 years, usually 3 to 5 years for tuberculoid leprosy and 9 to 12 years for lepromatous leprosy.

In the present time, leprosy is not the threat that has affected humankind for millennia (50). In 1991, the World Health Assembly advanced the goal to eliminate leprosy as a public health problem by the year 2000. The elimination goal was set to decrease prevalence below 1 case per 10,000 people (59). This goal was successfully achieved at a global level through an expansion of diagnostic services and Multi-Drug Therapy (MDT) availability with the support of local governments and non-governmental organizations (52, 58). However, in many countries and regions, the prevalence of leprosy and the detection rate of new cases remained high (50). In 2000, the World Health Organization (WHO) put forward the WHO Strategic Plan for Leprosy Elimination 2000-2005, focused on elimination at a national level, followed in 2005 by the Global Strategy for Further Reducing the Leprosy Burden and Sustaining Leprosy Control Activities 2006-2010 and, currently, the “Final Push” strategy for elimination of leprosy (59). In 1985, the prevalence of the disease was 5.2 million cases with cases occurring in 122 countries (66). By 2005, the global prevalence of the disease had decreased to between 200,000 - 300,000 and the number of countries involved continues to shrink (59). In recent years, further prevalence reduction seems more difficult to attain with many areas leveling out. As a result, there continues to be around 230000 new cases diagnosed every year since 2005. Detection of new cases remains concentrated in India, Brazil, Indonesia, and in other 40 countries. Sadly, at a global level the rate of grade 2 disability remains the same in 2013 as to the rate of 2010 (59).

Thus, leprosy continues to impose a substantial burden of disease in affected countries with continuing transmission as evidence of new cases detection continues. In addition, despite having received effective multi-drug therapy, many patients continue to experience the long-term consequences associated with nerve impairment and its secondary limb or ocular affection. Many patients endure recurrent or persistent leprosy reactions even after adequately completing multi-drug therapy (12).

CLINICAL MANIFESTATIONS

The variability of the immune response mounted by the host in response to infection with M. leprae will determine a spectrum of bacteriological, pathological, immunological and clinical features between two polar forms, tuberculoid and lepromatous leprosy (42):

Tuberculoid Leprosy

The disease is localized to one or few sites in the skin and large peripheral nerves. Skin lesions are asymmetrical, hypopigmented, with well-defined margins. Patients may present with defined plaques, irregular plaques, and healing centres. They are anaesthetic and dry. One or few peripheral nerves are commonly enlarged. In this form, CMI is at its highest and there are scant numbers of bacilli in the lesions.

Lepromatous Leprosy

Lepromatous Leprosy is the form of disease associated with an absence or low CMI response and massive bacillary multiplication. Skin lesions are of various types (nodules, papules, macules or diffuse infiltration) and are widely disseminated, bilaterally symmetrical, usually numerous and extensive. Nerve lesions are slow to appear but can lead to deformities, amputation, and disability. Patients have diffuse thickening of nerves with slow, symmetrical glove-and-stocking anesthesia.

Borderline Leprosy

Borderline Leprosy is characterized by a mixture of signs and symptoms of the polar forms, reflecting the instability of between bacillary multiplication and cellular immunity. This is the form of the disease associated with potential severe nerve involvement. The clinical diagnosis is based on careful examination of the skin for hypopigmented anesthetic patches and search for peripheral nerve involvement, which demands a thorough examination of the entire skin surface. Skin lesions may present as papules, nodule, and punched-out centres. Many nerves may be involved with a symmetrical pattern. Patients often have late neural thickening with asymmetrical anesthesia and paresis.

LABORATORY DIAGNOSIS

Its microscopic identification relies on the fact that M. leprae is acid- and alcohol-fast when stained with carbol-fuchsin. The microbiological diagnosis is made on slit-skin smears, taken from the edge of suspect lesions and from sites commonly affected (ear lobes) and stained by Ziehl-Neelson’s method. The density of bacilli is recorded as the Bacterial Index. For operational purposes, the results of skin smear are used to differentiate between paucibacillary (skin smears negative at all sites) and multibacillary (at least one positive skin smear at any site) leprosy (62). The biopsy of the skin in an affected area will describe the histological appearance associated with the immunological spectrum and will confirm the diagnosis.

SUSCEPTIBIITY IN VITRO AND IN VIVO

In the absence of techniques for culturing M. leprae in artificial media, it has been necessary to screen drugs in vivo for their antimicrobial activity against M. leprae. In 1960, Shepard discovered that inoculation of M. leprae into the mouse foot pad was followed by a limited multiplication of bacilli without any visible macroscopic lesion (45). This has been a milestone in the evaluation of antimicrobial activity against M. leprae, in particular to assess Minimal Inhibitory Concentration (MIC) and to distinguish bacteriostatic and bactericidal activities.

Single Drugs

Sulfones

Dapsone has been the most widely used among the anti-leprosy drugs, due to its low price, safety and effectiveness. Dapsone is the parent sulfone. Its structure is very similar to the structure of the sulphonamides. As an analogue of PABA, dapsone prevents its utilization for the synthesis of folic acid by competitive inhibition for dihydropteroate synthetase. The MIC, determined after inoculation in the mouse foot-pad system is 0.003 µg/ml (46). In man, a single dose of 100 mg gives a blood level of around 1.5 µg/ml, 500 times the MIC. At this dose, dapsone is weakly bactericidal against M. leprae. At lower doses (10 mg/day), the serum concentration is still higher than the MIC but dapsone is only bacteriostatic. Dapsone is rapidly and nearly completely absorbed when taken orally. It is then acetylated in the liver and slowly excreted through the kidneys. As acetylation is genetically determined, the half-life of the drug differs in individuals from 12 to 50 hours (average: 24 hours). Once in the body, dapsone distributes in skin, muscles, liver, kidneys and nerves.

Resistance to sulfones was first described in 1964 (39) and has since then become an increasing problem around the world (22). Resistance probably develops as a step-wise process of mutation (18) whereby mutant bacilli to increasing levels of dapsone are successively selected. Most resistance is secondary, appearing in multibacillary patients after 10 to 20 years of dapsone monotherapy. Primary resistance due to infection with dapsone resistant M. leprae is less frequent, and is usually present in areas of the world where dapsone has been used extensively (38).

Rifampicin

Discovered in 1967, rifampicin is a semi-synthetic derivative of rifamycin SV, a broad-spectrum antibiotic of complex macrocyclic structure produced by Streptomyces mediterranei. Rifampicin has a powerful activity both on M. tuberculosis and M. leprae.

All derivative products of rifamycin SV have a similar central macrocyclic structure, probably responsible for antibacterial activity. Rifampicin inhibits the DNA dependent RNA polymerase by fixation on the beta subunit of this enzyme, thus blocking mycobacterial RNA synthesis. The MIC is 0.3 µg/ml. After administration of one dose of 600 mg (10 mg/kg), a peak plasma concentration of 7 µg/ml is reached in 2-4 hours, which is highly bactericidal against M. leprae. The biological half-life is approximately 3 hours. In man, a single dose of 600 mg renders bacilli non viable after inoculation to mice, which corresponds to a bactericidal activity of 99% to 99.99% (41, 48).

Rifampicin resistance is rare, but has been observed in patients presenting a relapse after dapsone therapy and then treated for long periods with rifampicin alone (15, 20). Up to now, no case of primary resistance has been reported. Persisting viable bacilli have been isolated from patients receiving rifampicin alone or in combination regimens (51).

Clofazimine

Clofazimine is a substitute iminophenazine dye, which was synthesized in 1956 (Lamprene*, B-663) and first used in the treatment of leprosy in 1960 (4). It is a red crystalline substance, soluble in oil and ethanol but not soluble in water. The mode of action is not totally known. It is suggested that clofazimine inhibits DNA replication through fixation on mycobacterial DNA (10). The MIC in the mouse foot pad system could not be determined due to its persistence in tissues for a prolonged period of time. Clofazimine has a weak bactericidal activity. After 6 months of daily treatment with 100 mg, viable bacilli (after inoculation into mice foot-pads) are found in one third of patients (21). In addition, clofazimine has an anti-inflammatory effect, which is useful in the prevention and treatment of Erythema Nodosum Leprosum. A case of resistance to clofazimine has been reported, but to date, this has not been confirmed (57).

Fluoroquinolones

These nalidixic acid derivatives inhibit DNA gyrase, which is involved in DNA replication. Ofloxacin and pefloxacin have been shown to have an extremely powerful bactericidal activity on M. leprae: in multibacillary leprosy patients, 22 daily doses of 400 mg ofloxacin or 800 mg pefloxacin killed 99.99% viable bacilli present at the start of treatment (16).

Minocycline

Minocycline is the only tetracycline active against M. leprae. It acts on the ribosomal synthesis of proteins of M. leprae. In mice, it has a similar bactericidal activity to ofloxacin (11). In man, a daily dose of 100 mg kills more than 99% of viable bacilli in one month (25).

Clarithromycin

This new macrolide inhibits the synthesis of mycobacterial proteins. In mice, its bactericidal activity is similar to that of ofloxacin and minocycline (23). In man, the drug kills in one month more than 99% of viable bacilli (13, 25).

General

Treatment of leprosy has evolved considerably over the past 40 years and several effective drugs are now available, allowing for an excellent prognosis if given at an early stage of the disease. The principles of combined drug therapy have been well established and Multi-Drug Therapy (MDT) using dapsone, rifampicin and clofazimine has been recommended by WHO and widely used in practice (60). Long acting sulfamides, thioamides, thiacetazone and thiambutosine, which have a weak bactericidal activity, are no longer used. Fluoroquinolones, macrolides and cyclines have recently been demonstrated to have anti-leprosy activity, and have been introduced in the treatment of specific forms of leprosy.

Specific Drugs

Dapsone

Dapsone is usually formulated in 100 mg tablets. It is given daily at a single dose of 100 mg for adults and 2mg/kg body weight for children. A multitude of side-effects have been reported. Although rare when dapsone is used at appropriate dosages (100 mg/day), they occur much more frequently if higher doses are given (200-300 mg/day). They include headache, skin rash, fever, psychosis, gastrointestinal disorders, nephrotic syndrome, haemolytic anemia, agranulocytosis, hepatitis, peripheral neuropathy, methemoglobinemia, hypoalbuminemia. The idiosyncratic DDS (or sulfone) syndrome has been described since the early days of sulfone therapy and has been reported in leprosy patients (33). It usually develops within 6 weeks of the start of treatment and manifests as skin rash and/or exfoliative dermatitis, generalized lymphadenopathy, hepatosplenomegaly, fever and hepatitis. When this syndrome occurs, dapsone should be immediately discontinued. Corticosteroids may be of benefit.

A mild haemolysis has been regularly observed in leprosy patients receiving dapsone therapy, but severe anemia is rare and is dose-related. However, patients with G6PD deficiency may develop severe haemolytic anemia. Methemoglobinemia can occur in patients with a congenital deficiency in NADH-dependent methemoglobin reductase. It is usually not a problem with routine doses of dapsone, but may become severe in case of overdose. Peripheral neuropathies have been reported in patients taking high doses of the drug and are usually reversible when dapsone is discontinued. Agranulocytosis is a very rare but serious idiosyncratic effect of dapsone, which has been reported in individuals taking dapsone in combination with pyrimethamine for malaria prophylaxis (37).

Rifampicin

Rifampicin is usually administered in a single daily dose of 10 mg/kg, 600 mg in adults and 450 mg in persons weighing less than 35 kgs. Due to its marked bactericidal activity, rifampicin can be used intermittently, with doses ranging from 600 to 1200 mg and at intervals ranging from 1 week to 1 month (67).

After ingestion, rifampicin is rapidly absorbed on an empty stomach. It diffuses rapidly into tissues and the concentrations obtained are at least equal to serum concentration. It is distributed throughout the body, crosses the placental barrier and appears in breast milk. As the drug is lipid soluble, it has an excellent intra-cellular penetration. The drug is partially eliminated in urine, but most of it enters the entero-hepatic circulation where its reabsorption is interrupted by deacetylation in the liver. The drug usually produces a reddish-orange discoloration of urine, feces and lacrymal secretions, and patients should be warned of this aspect, which has no serious consequences, except staining of contact lenses.

Rifampicin is usually well tolerated. Toxicity depends both on the dosage and on the interval between doses. With daily treatment, a transient elevation of hepatic transaminases (up to 2 or 3 times the normal upper limit) is often observed. Sometimes, however, especially in cases of pre-existing hepatic disease or simultaneous administration of another hepato-toxic drug, transaminases may be grossly elevated. A flu-like syndrome can be observed when rifampicin is used intermittently (1-2 weeks intervals), and if doses exceed 10 mg/kg. This occurs most frequently when rifampicin is given at 1-2 weeks intervals but is not common when given either daily or once a month. Current WHO Multidrug Therapy recommends monthly doses (600 mg). Other immuno-hematologic disorders may occur, such as hypereosinophilia, interstitial nephritis, acute tubular necrosis, thrombocytopenia, haemolytic anemia, which demand immediate discontinuation of the drug. Other side effects include fatigue, headache, drowsiness, skin rash. Teratogenicity has not been demonstrated in humans. Due to its effect on hepatic microsomial enzymes, rifampicin increases hepatic metabolism of other drugs, such as corticosteroids, digoxin, quinidine, oral contraceptives and oral hypoglycemics (1).

Clofazimine

The current preparation of clofazimine is a microcrystalline suspension in an oil-wax base, which is absorbed at about 70%. The serum concentration is variable, 0.5 to 0.7 ug/ml after a daily dose of 100 mg (2). The drug is unevenly distributed in the body: as it is lipophilic, high concentrations have been reached in fatty tissues and in cells of the reticuloendothelial system. The serum half-life is around 10 days but the tissue half-life can be as long as 70 days. The exact mechanism of elimination is unknown, but very little is excreted in urine.

Clofazimine is available in gelatin capsules of 50 and 100 mg. The adult dose is 50 mg daily or 100 mg twice weekly and for children 1 mg/kg. Due to its long tissue half-life, administration of the drug can be adapted, such as the WHO recommended scheme of 50 mg/day supplemented by 300 mg once a month. The major side-effect of clofazimine is the red pigmentation of skin and conjunctiva, which varies with the initial skin color but is more troublesome in lighter skinned people. Pigmentation usually disappears in 1 to 2 years after stopping treatment. Itching, dryness and cracking of skin occur frequently. The more serious toxicity is with the gastro-intestinal tract, giving rise to crampy abdominal pain, nausea and diarrhea. These are less frequent, however, if capsules are given with food. High doses of clofazimine can cause severe abdominal pain. The drug appears to be safe in pregnancy but experience so far is limited.

Fluoroquinolones

Fluoroquinolones are rapidly absorbed in the gastro-intestinal tract and have high availability after oral administration. They are highly concentrated in respiratory tract tissues, secretions and inside macrophages. Amongst the various fluoroquinolones, ofloxacin achieves plasma concentrations higher than the minimal inhibitory concentration in human plasma. The adult dose for ofloxacin is 400 mg daily, and for pefloxacin, 800 mg daily. The main side effects include gastrointestinal disorders, joint pain, and photosensitivity. Fluoroquinolones can also induce neurological disorders, tendonitis and hepatitis. They are contraindicated in children, as well as in pregnant and lactating women. Digestive absorption is reduced if absorbed together with antacids. Fluoroquinolones are potentiated by concurrent use of theophylline.

Minocycline

Oral absorption is excellent, but decreases with anti-acids and calcium. The half-life is approximately 18 hours. Tissue diffusion is good, especially in bones, lungs and skin. The excreted product, in the biliary tract, is active. In man, a daily dose of 100 mg is well tolerated. Side effects include gastrointestinal disorders (nausea, vomiting, gastric pain, ulcers), photosensitivity, coloration of teeth in children (under 8), and acute vestibular dysfunction. Rarely, neutropenia, thrombopenia and hemolytic anemia are encountered. Minocycline is contra-indicated in children and in pregnant and lactating women. Due to photosensitivity, sun exposure must be discouraged. The oral dose in adults is 3mg/kg/day (14).

Clarithromycin

Oral absorption is variable, but serum concentration can be high. It is highly concentrated in macrophages and neutrophils. The half-life is variable. In man, given at a daily dose of 500 mg, the drug is well tolerated. Side effects include: gastro-intestinal disorders, skin rash, hepatitis. It can create acoustic disorders in patients suffering from renal insufficiency. The association with anti-histamine is formally contraindicated, due to the high risk of cardiac arrhythmia, and association with theophylline is not advised.

Combination Drug Therapy

Although a minority in number, patients with multibacillary (lepromatous) leprosy are the main source of infection with M. leprae and those in whom drug-resistant mutants are the most easily selected. In these patients, it has been estimated that there could be as many acid-fast bacilli, of which only 1% (109 to 1010) are viable (48). As M.leprae cannot be cultured in-vitro, it is difficult to establish the proportion of M. leprae mutants that are resistant to dapsone, clofazimine or rifampicin. By analogy with tuberculosis, the mean proportion of drug-resistant mutants within a wild strain of M. leprae was estimated to be 1 in 10 million organisms (17).

In order to cure a leprosy patient bacteriologically, Multi-Drug Therapy (MDT) must be capable of killing all viable organisms, the susceptible and the resistant mutants, and to prevent the selection of resistant mutants (17). Assuming that a mutant resistant to a given drug remains fully susceptible to another drug if the latter has a different mechanism of action, a combination of at least 2 drugs is required to kill the resistant mutants. In practice, in order to overcome primary and secondary resistance to dapsone, the recommendation is to use a combination of rifampicin, dapsone and clofazimine (60). Dapsone being poorly bactericidal must be given daily at a dose of 100 mg in adults. Clofazimine must be given at a daily dose of 50 mg, with a monthly supplementation of 300 mg. For rifampicin, it has been shown that a single dose of 600 mg kills more than 99% of susceptible organisms present at the start of treatment (47), which is equivalent to 3-6 months of daily treatment with dapsone and clofazimine. It was further shown that daily treatment with rifampicin was not more bactericidal than monthly treatment (51). As mutants resistant to dapsone and clofazimine are supposed to be fully susceptible to rifampicin, they are killed by the first dose of rifampicin, which has been shown to reduce the proportion of viable bacilli in multibacillary leprosy patients from 109 to 104. Thus the majority of susceptible organisms as well as the mutants resistant to dapsone and clofazimine have been eliminated after the first dose of rifampicin. The remaining rifampicin resistant mutants will be killed by daily doses of dapsone plus clofazimine (27). The combination dapsone plus clofazimine will kill the rifampicin resistant mutants and should be administered throughout the course of therapy (24).

In patients with multibacillary leprosy, the initial phase of chemotherapy considerably reduces the number of viable bacilli. The objective of the second phase of chemotherapy is then to eliminate the remaining 104 viable drug susceptible bacilli, avoid selection of bacilli secondarily resistant to rifampicin and prevent relapse after stopping treatment. It has been shown that the time required to clear 104 bacilli is about 7 years for a multibacillary case of leprosy with maximum bacterial load (17, 51). Data from Mali suggest that the shorter the duration of treatment, the earlier the occurrence of relapses (34). In addition, relapses were more frequent in subjects highly bacilliferous at the start of treatment. In leprosy control programs, it is difficult to adapt the length of treatment to the bacterial load of each patient. In addition, for operational purpose, there is a need to standardize the length of treatment for each of the main categories of leprosy patients (pauci- or multi-bacillary). The treatment regimens recommended for multi-drug therapy are thus a compromise between theory and operational constraints.

Summary of drug choices and duration of therapy treatment of the clinical forms of leprosy (12, 32, 56, 61):

Paucibacillary leprosy

Rifampicin 600 mg monthly, for 6 months supervised along with dapsone 100 mg once daily, unsupervised, given for 6 months. Rifampin is given once a month. No toxic side effects have been reported in the case of monthly administration.

Multibacillary leprosy

Rifampicin 600 mg monthly, supervised (53); plus dapsone 100 mg once daily, unsupervised; clofazimine 50 mg daily, unsupervised; clofazimine 300 mg monthly, supervised. All three drugs are given for 24 months in a 36 months period or until smear negativity is obtained. Clofazimine is most active when administered daily. The drug is well tolerated. The drug causes brownish black discoloration and dryness of skin. However, this disappears within few months after stopping treatment. The rationale for using clofazimine with a monthly-supervised dose and a daily-unsupervised dose is due to the fact that clofazimine is a repository drug (slow excreted from the body). A monthly loading dose ensures an optimal amount of clofazimine is maintained in body tissues even if the patient occasionally misses daily doses.

Single Skin Lesion Paucibacillary leprosy

For adults the standard regimen is a single dose triple-combination of Rifampicin 600 mg, Ofloxacin 400 mg, and Minocycline 100 mg.

Effectiveness of Multi-Drug Therapy

The most important indicator for the effectiveness of a chemotherapeutic regimen is the rate of occurrence of relapse following successful completion of the scheduled course of treatment. Documented relapse rate by WHO from a number of control programs, shows that the relapse rate is very low (0.1% per year for paucibacillary forms and 0.06% per year for multibacillary forms).

Since 1982, multi-drug therapy has been widely implemented in all leprosy endemic areas. By mid 1996, 91% leprosy patients in the world were being treated with WHO recommended multi-drug therapy (63). These regimens proved to be well tolerated, highly effective and relapses reported rarely (1.09% in paucibacillary and 0.74% in multibacillary leprosy over a 9 year period) (62). Based on reported observations, clinical studies and field trials, the WHO Expert Committee on leprosy proposed that duration of multi-drug therapy be shortened to 12 months for multibacillary leprosy (64). Although not unanimously approved, and a matter of controversy, this shortened combination therapy is now widely implemented (36, 54).

In most affected countries, leprosy control programs have now been integrated into general health services, and vertical programs have almost disappeared. In order to further simplify the delivery of drugs by general health services and improve patients’ adherence to the treatment, new drug combination regimens have been proposed and tested, using newly discovered drugs active against M. leprae, such as clarithromycin, minocycline and ofloxacin. Thus, several combinations of these drugs have been tested in nude mice and were showed to display high bactericidal activities (28). A single dose of clarithromycin plus minocycline, with or without ofloxacin, was reported to display a bactericidal activity similar to that of one month of dapsone plus clofazimine in multibacillary patients in Mali (26). However, 45% of the patients experienced gastro-intestinal side effects related to the use of clarithromycin, making this combination unsuitable for routine use. Other combinations of drugs were then tested. Thus, a single pulse of rifampicin (600mg) plus ofloxacin (400 mg) plus minocycline (100 mg) was shown to kill 96.8, 9% of viable M. leprae in the mouse model and more than 99% in humans (28). Based on these preliminary results, the efficacy of the 3 drugs, given as a single dose combination, was assessed in the field for the therapy of single-lesion paucibacillary leprosy in a double-blind controlled trial (49). The comparison was between the same combined dose of rifampicin, ofloxacin and minocycline (ROM) and the WHO standard multi-drug therapy regimen for paucibacillary leprosy. More than 99% of the patients exhibited clinical improvement, but this was significantly more marked amongst patients treated with standard multi-drug therapy than in those treated with single rifampicin, ofloxacin and minocycline (ROM) dose. However, in view of the good results obtained in those treated with the single pulse of ROM, and due to its strong operational advantages and low-cost, the WHO Expert Committee concluded that a single dose of the combination of rifampicin, ofloxacin and minocycline was an acceptable and cost-effective regimen for the treatment of paucibacillary leprosy patients with a single skin lesion (65). However, the methods and results of the trial raised many questions and it is advised to implement single-dose rifampicin, ofloxacin and minocycline (ROM) treatment in paucibacillary leprosy with care (31).

Alternative Therapy

In view of the proven efficacy of WHO-multi-drug therapy, the priority is to detect cases as early as possible and implement multi-drug therapy as rapidly and as extensively as possible in endemic areas. Patients’ adherence to long courses of treatment remain however a programmatic problem. With the drugs presently used in multi-drug therapy, there is little hope of shortening further the overall duration of treatment but compliance could be improved by developing a regimen capable of being given on a monthly basis. Newer drugs with strong bactericidal activity are needed in order to develop fully supervised intermittent regimens. Two agents are presently being investigated, moxifloxacin and rifapentine, and experiments in the mouse-foot pad model are promising. Their use would improve patients’ adherence to long courses of treatment (7).

ADJUNCTIVE THERAPY

A major problem in leprosy is the development of reactions, which if not diagnosed and treated early in their course, it will result in disabilities (3, 43).

Type 1 Reversal Reaction

This reaction is characterized by episodes of increased inflammation at sites where bacilli exist, in skin and nerves among patients with borderline leprosy. Edema of the face, hands and feet may occur. Inflammation in the nerves causes pain, tenderness and functional impairment, which can lead to severe disability (29, 30).

Type 2 Reaction or Erythema Nodosum Leprosum

Type 2 reactions occurs in multibacillary forms of leprosy. They are thought to be immune complex mediated. Erythema nodosum leprosum is characterized by the appearance in the skin of painful erythematous nodules, dome-shaped, shiny and tender, which can secondarily ulcerate. Systemic involvement is frequent with fever, iritis, orchitis, nephritis, dactylitis, arthritis and enlargement of nerves.

These reactions (and particularly Type 1 reactions) need to be recognized and treated promptly in order to avoid irreversible loss of nerve function (3, 30). Mild reactions, in which pain or tenderness are absent and skin lesions are minor, can be distinguished from severe reactions, characterized by the presence of severe neuritis with anesthesia and/or paralysis (type 1) or ulceration of skin accompanied by fever, iritis, and arthritis (type 2). Severe reactions constitute a medical emergency and anti-inflammatory treatment must be started immediately if disability is to be avoided:

Corticosteroids

In type 1 reaction, prednisolone is usually given at a starting dose of 40-80 mg per day according to severity. The dose is thereafter reduced by 5-10 mg every two to four weeks according to the patient’s response, which is best assessed clinically and through careful testing of nerve function. Immobilization of the affected limb is helpful to relieve pain and protect against nerve function loss. As corticosteroids suppress the immune response, it is necessary to continue anti-leprosy treatment while they are given or restart dapsone or clofazimine monotherapy if multi-drug therapy has been completed. Studies are presently conducted to assess whether non-steroidal cytotoxic drugs can be used for long-term management of Type 1 reactions.

Thalidomide

Thalidomide is the drug of choice for the treatment of Erythema Nodusum Leprosum. Thalidomide and its active analogues are thought to work by partial inhibition of synthesis of tumor necrosis factor alpha. This drug is given at a daily dose of 400 mg until reaction is controlled and then reduced gradually to 50 mg daily. This drug must never be given to women of childbearing age due to its disastrous teratogenic effects, causing phocomelia in the fetus if taken during the first trimester of pregnancy. If contra-indicated, prednisolone should be given at a dose of 20-40 mg per day and the dose adjusted according to response. It also causes neuropathy. which may not be recognized in the context of the peripheral neuropathy caused by leprosy. Nevertheless, in many settings, prednisone or prednisolone are used instead of thalidomide with adequate anti-inflammatory responses.

ENDPOINTS FOR MONITORING THERAPY

The introduction of multi-drug therapy has had far reaching effects on the structure and strategy of leprosy control programs worldwide. The shortened course and the requirements for supervising monthly doses of rifampicin have greatly reduced the problem of compliance. Patients with leprosy may still, however, develop disabilities due to nerve damage, usually related to the development of reactions (29, 30). Early detection of nerve damage by regular testing of nerve function is therefore a mandatory complement to multi-drug therapy. Systematic surveillance during and after treatment is recommended to detect early signs of reactions so as to prevent disability. The optimum management of leprosy thus involves a multi-disciplinary approach, including antimicrobial chemotherapy, physiotherapy, prevention of disability as well as reconstructive surgery when deformity and disability are present. With the even shorter duration of treatment, it is of utmost importance to continue regular surveillance of treated patients in order to prevent the development of disabilities and ensure appropriate care after cure (58).

VACCINES

The Bacillus Calmette–Guérin (BCG) vaccine widely used for protection against tuberculosis does provide some moderate protection against leprosy, with estimates ranging from 2-90% (44). Unfortunately, a second dose of BCG in school age children (1999-2006) (BCG-REVAC) in Brazil (Manaus) did not confer protection against leprosy among household contacts (8).

PREVENTION

Antimicrobial Prophylaxis

Post-exposure prophylaxis with one dose of rifampin may reduce detection rates of new patients by about 50-60% (50). Prophylaxis with Dapsone for close contact of leprosy patients is not generally recommended. Dapsone appears to decrease the prevalence of tuberculoid leprosy, but only forestalls the onset of lepromatous leprosy.

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