Leprosy: Treatment and prevention

INTRODUCTION — Leprosy (also known Hansen's disease) is an infectious disease caused by Mycobacterium leprae and Mycobacterium lepromatosis that involves the skin and peripheral nerves.

M. leprae and M. lepromatosis comprise "Mycobacterium leprae complex" [1]. The DNA sequences of M. leprae and M. lepromatosis differ enough to distinguish them as separate species, but they share many similarities (both are obligate intracellular parasites with a tropism for nerves) and cause the same clinical disease [2].

Leprosy is an important global health concern. Contrary to popular folklore, leprosy is not highly contagious, and very effective treatment is available [3-6]. Early diagnosis and treatment are necessary to minimize the likelihood of disability involving the eyes, hands, and feet due to neuropathy as these are often not reversible and may require lifelong care [7].

Not all patients have access to appropriate therapy and not all countries have the infrastructure to support leprosy control efforts [8]. Worldwide, the number of dedicated leprosy programs is declining, and international migration is bringing patients to nearly every region [9].

The treatment and prevention of leprosy are reviewed here. The epidemiology, microbiology, clinical manifestations, and diagnosis of leprosy are discussed separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

CLASSIFICATION — Leprosy has been classified into the following categories based on the Ridley-Jopling classification (figure 1):

●Tuberculoid (TT)

●Borderline tuberculoid (BT)

●Mid-borderline (BB)

●Borderline lepromatous (BL)

●Lepromatous (LL)

●Indeterminate (I)

The classification of leprosy is discussed in further detail separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Classification and terminology'.)

TREATMENT — Treatment of leprosy consists of multiple-drug therapy (MDT) to prevent development of resistance [6]. MDT is active against M. leprae and rapidly renders the patient noninfectious; in addition, use of MDT reduces the likelihood of emergence of drug resistance [10,11]. First-line medications include dapsone, rifampin, and, for lepromatous disease, clofazimine. Used in combination, these have proven to be effective [12]. Conventional anti-leprosy therapy is effective in treating both M. leprae and M. lepromatosis [13-15].

Promine, a sulfone, was the first antimicrobial agent successfully used to treat leprosy; subsequently, efficacy was also demonstrated with dapsone, its parent compound [16-18]. After many years of monotherapy with these agents, drug resistance was observed [19,20].

In the 1980s, a World Health Organization (WHO) study group met to consider multidrug therapy for leprosy, mindful of the experience with the development of drug resistance after monotherapy for tuberculosis. In light of the "imperative need for therapeutic regimens," the WHO published guidelines in 1982 with an empiric recommendation for use of dapsone and rifampin for treatment of tuberculoid leprosy and addition of clofazimine for treatment of lepromatous disease [3].

Subsequent WHO guidelines were published in 1998 and 2018 [4,6].

The efficacy of the individual agents had been demonstrated clinically and in mouse studies and was subsequently confirmed in vitro [21-23]. No controlled trials comparing drug combination regimens have been done; designing trials for treatment of a noncultivable pathogen is complicated by the lack of an accurate quantitative endpoint. In addition, a very long observation period is required for identification of relapse (approximately 15 to 20 years) [18]. (See 'Relapse' below.)

Selecting a regimen — Our approach to treatment of leprosy is as follows:

●For patients with tuberculoid disease, we favor treatment with dapsone (100 mg daily) and rifampicin (600 mg daily) for a duration 12 months.

●For patients with lepromatous disease, we favor treatment with dapsone, rifampicin, and clofazimine (50 mg daily) for a duration 24 months.

This approach is consistent with the United States National Hansen's Disease Program (NHDP) but differs from guidelines issued by the WHO.

We are in agreement with the treatment approach advocated by the NHDP. This approach follows the WHO 1982 guidelines [3] and advocates the treatment regimen summarized in the tables (table 1 and table 2). Specifically, the NHDP favors a longer duration of therapy (as in the 1982 WHO recommendation, compared with subsequent WHO guidelines) and advocates daily rather than monthly administration of rifampin [5]. The duration of treatment recommended by the WHO in 1982 was 6 to 12 months for tuberculoid disease (TT and BT) and 24 months for lepromatous disease (BB, BL, and LL) [3].

The 1998 WHO guidelines reduced the recommended duration to 6 months and 12 months, respectively [4]. The shortened durations reflect cost considerations for resource-limited settings; however, shorter treatment regimens have been associated with a greater incidence of relapse [24]. Based on these guidelines, treatment for patients with TT consists of dapsone (100 mg daily) and rifampin (600 mg rifampin once monthly) for 6 months; treatment for patients with LL consists of dapsone (100 mg daily), clofazimine (50 mg daily plus 300 mg once monthly), and rifampin (600 mg once monthly) for 12 months.

The 2018 WHO guidelines recommend uniform MDT; the recommendations for treatment duration from 1998 are retained [6]. The approach consists of administration of three drugs (rifampin, dapsone, and clofazimine) to all patients, regardless of disease classification. The change consists of addition of daily clofazimine to regimen for patients with paucibacillary disease; the approach for patients with multibacillary disease is unchanged. It has been proposed that use of uniform MDT reduces the likelihood of undertreating patients with multibacillary disease who may be misclassified as having paucibacillary disease; however, this approach is controversial since it entails routine use of clofazimine which may be unnecessary in some patients.

Alternative agents for treatment of leprosy include minocycline, ofloxacin, levofloxacin, clarithromycin, and moxifloxacin. Evidence for the efficacy of newer drug combinations or shorter regimens is weak [25]. Earlier attempts to treat patients with "single-lesion paucibacillary disease" with a single-dose combination of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg) were based on a multicenter trial in which this regimen demonstrated slightly less clinical improvement compared with the standard WHO paucibacillary (PB) regimen during 18 months of follow-up [10,26]. Another report indicated that one month of rifampin plus ofloxacin was insufficient for the treatment of lepromatous (multibacillary [MB]) disease [27].

Drugs for treatment of leprosy

Overview — In the United States, medication for the treatment of leprosy are provided free of charge by the NHDP (1-800-642-2477) [9]. Outside the United States, the WHO distributes medications through the Ministry of Health in each country [28].

●Dapsone – Dapsone is inexpensive and generally well tolerated in the doses used for the treatment of leprosy. Adverse effects include dapsone hypersensitivity syndrome, methemoglobinemia, and agranulocytosis. Shortened red cell survival is common with dapsone, though severe hemolytic anemia is uncommon except in those with a severe glucose-6-phosphate dehydrogenase (G6PD) deficiency; all patients should be screened for G6PD deficiency before receiving dapsone. Because the antibacterial activity of dapsone is inhibited by p-aminobenzoic acid (PABA), it is thought that dapsone has a mechanism of action similar to that of the sulfonamides, which involves inhibition of folic acid synthesis. (See "Methemoglobinemia" and "Drug-induced neutropenia and agranulocytosis" and "Drug-induced hemolytic anemia".)

A dose of 100 mg daily is weakly bactericidal against M. leprae, but such a dose exceeds the minimum inhibitory concentration (MIC) of the organism by a factor of about 500. Such doses even inhibit the multiplication of M. leprae mutants with low to moderate degrees of dapsone resistance. The maximum dose should be used from the start and should not be reduced during immunologic reactions. Dapsone resistance is generally reported in areas where monotherapy has been used; it is extremely rare in the United States [29].

●Rifampin – Rifampin is the most bactericidal drug available for the treatment of leprosy. An estimated 99.999 percent of bacilli are killed with three monthly doses. The standard dose in the United States dose is 600 mg daily, but even a single dose of 600 mg monthly, as used in the WHO regimens, is highly bactericidal. Rifampin binds the DNA-dependent RNA polymerase complex, uncoupling transcription. The target for rifampin is the beta subunit of the RNA polymerase encoded by rpoB61.

Toxicity of the drug is relatively low but is related to the size of the dose and the interval between doses. The standard doses for leprosy have proven relatively nontoxic, although occasional cases of renal failure, bone marrow suppression, "flu-like" syndrome, and hepatitis have been reported. Daily administration of rifampin has major effects on drug metabolism by the liver cytochrome 3A4 (CYP3A4), which greatly affects other medications such as oral contraceptives, corticosteroids, and HIV protease inhibitors, among many others. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

●Clofazimine – Clofazimine is well tolerated in the standard dose of 50 mg daily used for leprosy. The major effect seen is pigmentation of the skin (especially within skin lesions), since the drug is lipophilic and accumulates in the lipid-rich cell wall of M. leprae. At higher doses (200 mg daily), hyperpigmentation may be noticeable within four weeks; at lower doses, it may take four to six months. Clofazimine causes phototoxicity, which can accelerate darkening of the skin with sun exposure. This pigmentation usually clears within one to two years after treatment is discontinued. Some patients are reluctant to take clofazimine because of the pigmentation but will usually accept it if the temporary nature of the pigmentation and the benefit of reducing the likelihood of a debilitating treatment reaction are carefully explained. The higher doses of clofazimine (up to 300 mg daily) sometimes used for the control of reactions may occasionally produce severe gastrointestinal side effects.

The mechanisms of action of clofazimine are not known. The drug is weakly bactericidal against M. leprae, but the combination of clofazimine and dapsone is much more active than either drug alone, killing 99.999 percent of bacilli in mouse studies within three months [30].

Clofazimine is not available in pharmacies in the United States. It is classified by the US Food and Drug Administration (FDA) as an investigational drug. Requests for clofazimine to treat leprosy should be directed to the NHDP (an agency within the Department of Health and Human Services), which holds the investigational new drug protocol for this indication, at 1-800-642-2477 (phone) [31].

●Minocycline – Minocycline is the only tetracycline with significant activity against M. leprae. This may be due to its lipophilic properties, which allow the drug to penetrate cell walls. It is bactericidal for M. leprae to a somewhat greater degree than clarithromycin but much less so than rifampin. Minocycline was very effective when given as monotherapy for two months in a small series of eight lepromatous or borderline lepromatous patients, although monotherapy is not recommended [32]. Minocycline inhibits protein synthesis via reversible binding at the 30S ribosomal subunit, thereby blocking the binding of aminoacyl-transfer RNA to the mRNA ribosomal complex. Side effects include discoloration of teeth in children, occasional pigmentation of the skin and mucous membranes, gastrointestinal complaints, and central nervous system (CNS) toxicity, including dizziness and unsteadiness.

●Macrolides – Several macrolides have been evaluated for activity against M. leprae; clarithromycin is the only effective agent. The drug has potent bactericidal activity but is less bactericidal than rifampin. At a dose of 500 mg daily in leprosy patients, 99 percent of M. leprae are killed in 28 days and 99.9 percent by 56 days [33]. The drug acts by inhibition of bacterial protein synthesis by linking to the 50S ribosomal subunit, thereby preventing elongation of the protein chain. Gastrointestinal irritation, nausea, vomiting, and diarrhea are the most common adverse effects, but they do not usually necessitate discontinuation of the drug.

●Fluoroquinolones – Ofloxacin has good antibacterial activity and is the most widely accepted fluoroquinolone for treatment of leprosy [30]. It acts by interfering with bacterial DNA replication by inhibiting the A subunit of the DNA gyrase. A single 400 mg dose has bactericidal activity against M. leprae, although less than that demonstrated by a single dose of rifampin, and two doses are capable of killing 99.99 percent of the viable M. leprae. Levofloxacin, the active L-racemer of ofloxacin, has replaced ofloxacin in many United States formularies. Moxifloxacin is also highly bactericidal against M. leprae; further study of rifampin and moxifloxacin as combination short-term therapy is needed [34,35]. Ciprofloxacin is not active against M. leprae (see "Fluoroquinolones").

Drug resistance — The epidemiology of drug resistance is discussed separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Drug resistance'.)

We are in agreement with the WHO 2018 guidelines for treatment of drug-resistant leprosy, as follows [6]:

●Patients whose isolate demonstrates rifampicin resistance may be treated using at least two of the following second-line drugs: clarithromycin, minocycline, or a fluoroquinolone (ofloxacin, levofloxacin, or moxifloxacin), plus clofazimine daily for 6 months, followed by clofazimine plus one of the second-line drugs daily for an additional 18 months.

●Patients whose isolate demonstrates resistance to both rifampicin and fluoroquinolones may be treated with the following drugs: clarithromycin, minocycline, and clofazimine for 6 months followed by clarithromycin or minocycline plus clofazimine for an additional 18 months.

Clinical response and follow-up — The erythema and induration of skin lesions may diminish within a few months of initiating therapy. It may take a few years for cutaneous lesions to resolve fully, depending on the initial number of lesions and severity of infection. Most lesions heal without scarring.

Once killed, dead bacilli are removed from the tissues very slowly; some may persist in the tissues for several years (picture 1) [36]. Since M. leprae and M. lepromatosis cannot be grown in culture and its viability cannot be assessed in biopsies, a definitive bacteriologic endpoint for treatment is not available. The presence of bacilli in smears or biopsies during and after treatment does not, in itself, indicate treatment failure or drug resistance. There is no evidence that prolonged antimicrobial treatment enhances the removal of dead M. leprae from tissues.

Given the lack of a definitive therapeutic endpoint, assessing compliance is especially important in assessing completeness of treatment. Laboratory evidence indicates that M. leprae are killed rapidly after exposure to rifampin and the other drugs used [37]. Experience with multidrug therapy has provided good evidence of cure with very few relapses using NHDP or WHO protocols with one to two years of treatment [7]. Therefore, if adherence to the well-established MDT protocols is good, killing of the bacilli and resolution of the lesions can be expected.

While on treatment, the first follow-up visit should be done in two to four weeks to evaluate for side effects of medications. After that, routine follow-up visits should be scheduled every three months. Visits should consist of a clinical examination, including assessment of the skin, nerves, limbs, and eyes, as well as laboratory studies to assess drug toxicity. Patients should report any new skin lesions, sensory or motor loss, eye symptoms, reactions, or other complaints.

Disease progression that occurs during therapy is almost always due to poor adherence to treatment. Therefore, patient education is an important part of each visit; compliance with a prolonged drug regimen is unlikely unless the patient fully understands the necessity for it. Cooperation of the family is also important.

For areas of the hands and feet where sensation has been lost, patients need to be taught to evaluate these areas regularly for evidence of injury and to obtain treatment promptly. Special protective shoes may be needed to avoid injury or ulceration. Motor loss resulting in deformities may require corrective surgery.

Examination of the eyes should include assessment of lid closure, cornea, and conjunctiva [38]. Complex problems such as iridocyclitis should be managed by a specialist. Corneal anesthesia and lagophthalmos require protective measures and corrective surgery.

In lepromatous (MB) cases, skin biopsies from the same lesion can be performed at one to two year intervals to assess the response to treatment by evaluating the reduction of inflammation and the decline of bacilli in the tissues. Processing and interpretation of biopsies for this purpose are available from the NHDP at no cost.

Routine laboratory studies to assess drug toxicity while on treatment include a complete blood count, urinalyses, creatinine, and liver function tests (table 3). Drug toxicity is relatively uncommon after the first year of treatment, and serious toxicity may manifest clinically before it is detected in the laboratory. Asymptomatic liver enzyme elevation of up to three times normal is acceptable.

After completion of treatment, annual follow-up for three more years is warranted for patients with tuberculoid disease and for five more years is warranted for patients with lepromatous disease. Patients should be advised to return for evaluation if new lesions or other problems develop.

TREATMENT OF IMMUNOLOGIC REACTIONS — Immunologic reactions are systemic inflammatory complications that occur either before treatment (some patients initially present for medical attention in the setting of a reaction), during treatment, or months to years after treatment has been completed [39]. A general feeling of fatigue, malaise, and fever may be present. Other manifestations include neuritis, arthritis, iritis, and nasopharyngeal symptoms. The inflammation associated with reactions can lead to severe nerve injury with subsequent paralysis and deformity. Immunologic reactions are discussed further separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Immunologic reactions'.)

In general, antimicrobial therapy should be continued in the setting of immunologic reactions, and patients should be reassured that the symptoms are not a reaction to the medications. Options for treatment of immunologic reactions include prednisone with or without other anti-inflammatory agents. Use of prednisone should prompt reduction in rifampin administration from 600 mg daily to 600 mg once monthly. Patients should be monitored carefully for neuropathy or neuritis and treated aggressively if these develop or worsen. Tapering of prednisone and other anti-inflammatory agents is empiric, based on clinical response.

Progression of the infection may occur in cases of noncompliance or drug resistance. Clinically, skin lesions may remain unchanged or may appear to worsen (with erythema and swelling) during the first year of treatment. In the setting of true disease progression, skin biopsies may demonstrate an increase in bacterial load, but this is difficult to document unless the biopsies are taken from adjacent sites of the same lesion. Drug resistance in leprosy is rare; in general, inadequate response to treatment is almost always due to inadequate adherence. Moreover, new lesions are almost always due to immunologic reactions, for which there are no well-established laboratory markers. (See 'Drug resistance' above.)

Type 1 reaction (T1R, reversal reaction) — Clinical manifestations of T1Rs are described separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Type 1 reaction (T1R, reversal reaction)'.)

Mild reactions without neuritis, ulceration, or other severe symptoms can be managed with supportive care. Severe T1Rs with neuritis require prompt treatment with corticosteroids to avoid permanent nerve damage [40]. Prednisone (40 to 60 mg/day) should be started and slowly tapered when the reaction has been controlled (in general, from three months in borderline tuberculoid to nine months in borderline lepromatous) [41]. Occasional patients with severe, protracted reactions require extended corticosteroid treatment for several additional months due to severe nerve pain, and some data suggest that higher doses and longer duration are more beneficial in ameliorating pain and other inflammatory symptoms than lower doses and shorter duration of corticosteroid treatment [42]. However, a review of clinical trials has demonstrated that prolonged corticosteroid regimens of many months do not provide long-term functional neurologic benefits for most patients [43]. No long-term benefit has been associated with prophylactic corticosteroid treatment for prevention of T1Rs [44]. In patients with concomitant diabetes, methotrexate may be used as a steroid sparing regimen [45].

Cyclosporine may be a useful second-line treatment for severe T1Rs in patients not responding to or unable to take corticosteroids [46]. It has been demonstrated to improve sensory nerve impairment and skin lesions in small numbers of patients in Brazil, Ethiopia, and Nepal; some significant toxicity was also noted [47,48]. Further study is needed to determine optimal dosing and to compare the efficacy and toxicity with corticosteroids.

Type 2 reaction (T2R, erythema nodosum leprosum, ENL) — Clinical manifestations of T2Rs are described separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Type 2 reaction (T2R, erythema nodosum leprosum, ENL)'.)

Mild reactions without neuritis, ulceration, or other symptoms can be managed with supportive care.

Severe T2Rs with neuritis and systemic symptoms require prompt treatment with corticosteroids to avoid permanent nerve damage. Prednisone (40 to 60 mg/day) should be started and quickly tapered (over a two-week period) when the reaction has been controlled; in the absence of clinical response, higher doses of prednisone may be administered. A relatively short course may be sufficient, but the reaction can recur and intermittent symptoms may continue for a year or more. If prolonged therapy will be needed in such cases, transitioning prednisone dosing to an every-other-day schedule may diminish steroid side effects [49].

Prolonged use of high doses of corticosteroids for both T1R and T2R entails the risk of many serious side effects.

Methotrexate (7.5 to 20 mg weekly), together with low doses of corticosteroids, may be effective as a steroid-sparing agent for treatment of leprosy reactions [50]. Further study of methotrexate for management of leprosy reactions is ongoing.

Clofazimine is not useful for the management of acute T2R, but may be of value in chronic cases. It is generally increased to a dose of 300 mg daily for four weeks and tapered slowly after response to 100 mg/day within 12 months. Gastrointestinal complaints may limit the use of higher doses. The clofazimine component of the multibacillary (MB) regimen may have some protective effect in preventing reactions since T2R appears to have become less common after the introduction of multiple-drug therapy. Clofazimine is not available in pharmacies and in the United States can only be obtained through the National Hansen's Disease Programs (NHDP; phone 1-800-642-2477).

Thalidomide is very effective in treating type 2 leprosy reactions [51], but teratogenicity limits its use in women of childbearing age. Of note, the efficacy of thalidomide in treating T2Rs is the only reason it has not been completely banned. Thalidomide is approved for marketing only under a special restricted distribution program approved by the US Food and Drug Administration (FDA) called "Risk Evaluation and Management Strategy" (REMS). Under this restricted distribution program, only prescribers and pharmacists registered with the program are allowed to prescribe and dispense the product. In addition, patients must be advised of, agree to, and comply with the requirements of the REMS program in order to receive the drug.

Thalidomide is administered initially in a dose of 300 to 400 mg daily; frequently, this regimen controls the reaction within 48 hours. Subsequently, the dose should be tapered to a maintenance level, generally around 100 mg daily; every few months, attempts are made to taper off the drug. To control erythema nodosum leprosum, thalidomide may be continued for several years. Development of neuropathy should prompt immediate discontinuation. In the authors' experience, a few patients with severe, prolonged T2Rs have continued to use thalidomide for up to 10 years.

Management of the Lucio phenomenon (necrotizing vasculopathy in patients with longstanding untreated lepromatous leprosy) requires antimicrobial therapy and corticosteroids as well as skin and wound care comparable with that given for extensive burns [52].

Alternative agents — Cytokines and their inhibitors are not routinely used for the treatment of leprosy or associated immunologic reactions; prospective data are lacking. Successful use of tumor necrosis factor-alpha (TNF-a) for management of rare cases of severe T2R has been described; however, these agents should be used cautiously and with close monitoring. In one review, use of TNF-a inhibitors was successful for treatment of four patients with intractable T2R; however, among 10 patients with arthritis or other conditions treated with TNF-a inhibitors, use of these agents was a risk factor for development of leprosy [53]. In addition, we are aware of unpublished cases in which use of these agents was not successful for management of T2R [54].

Experimental treatment of lepromatous leprosy by intralesional injection of recombinant interferon-gamma [55,56] or interleukin 2 [57] has demonstrated some evidence of improvement [58] but has also been associated with the development of T2R in an unusually high percentage of patients [59].

Other immunosuppressive drugs have been tested in the treatment of T2Rs, including cyclosporine, azathioprine, methotrexate, pentoxifylline, and mycophenolate mofetil, but no consistently beneficial results have been observed [46].

OTHER TREATMENT ISSUES

Relapse — Relapse of leprosy is relatively rare and must be distinguished from immunologic reaction (which is more common). The World Health Organization has reported a slowly increasing trend in the number of relapses, with 3120 cases worldwide in 2009 (1.3 percent of the number of new cases reported) [7].

Most relapses occur 5 to 10 years after completion of treatment. Relapse is more likely to occur in the setting of incomplete treatment or a very high bacterial load at the onset of treatment [60]. During true relapse, the tissue bacterial load generally rises steadily. The bacterial load may be expressed as bacteriologic index (BI), which is the number of bacilli per 100x field, expressed as a logarithmic scale (over 1000 bacilli per average field = 6+; 100 to 1000 bacilli = 5+, etc) [61]. An increase in the biopsy or skin smear BI of 2 or more indicates probable relapse [62].

Relapse can be distinguished from immunologic reaction in that the latter should improve after a short course of prednisone. (See 'Treatment of immunologic reactions' above.)

There is little evidence to guide the approach to retreatment after relapse. In general, treatment consists of reinitiating the same regimen used for initial therapy [62]. Patients who presented initially with tuberculoid (paucibacillary [PB]) disease but relapse with lepromatous (multibacillary [MB]) leprosy should be retreated with an MB regimen. Drug resistance is extremely unlikely to have developed as long as the original M. leprae strain was fully sensitive to the drugs used, although there is no role for baseline testing of drug resistance. When indicated, testing for mutations can be done from paraffin-embedded tissues taken at the time of diagnosis (ie, before treatment) and at the time of suspected relapse or resistance. (See 'Drug resistance' above.)

Leprosy and HIV — There has been no increase in leprosy in regions where HIV is prevalent. In patients coinfected with M. leprae and HIV, initiation of antiretroviral therapy may trigger a type 1 reaction (T1R); this is a manifestation of the immune reconstitution inflammatory syndrome [63-65]. (See "Immune reconstitution inflammatory syndrome".)

The response to leprosy treatment in HIV-infected individuals appears to be comparable with the response in HIV-uninfected individuals [65].

Leprosy in pregnancy — Immunologic reactions appear to occur more frequently in pregnant and postpartum women [66-68]. In two small series, such reactions were observed in up to 38 percent of patients [69,70]. Type 2 reactions were observed more frequently during pregnancy; T1Rs were observed more frequently in the postpartum period.

Management of leprosy and immunologic reactions in pregnancy is the same as described above for other patients. Regimens of all medications must be modified appropriately if the mother is breastfeeding. (See 'Treatment' above.)

PREVENTION

General principles — Control measures for leprosy include clinical management of active cases as well as contact management. Household contacts should be evaluated annually for evidence of disease for at least five years and should be educated to seek immediate attention if suspicious skin or neurologic changes develop. In the United States, free diagnostic clinics are available [71]. Issues related to prophylaxis are discussed below. (See 'Prophylaxis' below.)

Vaccination with Bacillus Calmette-Guérin (BCG) is partially protective for leprosy; a single dose appears to be 50 percent protective, and two doses further increase protection [72,73]. BCG is administered at birth in most countries with high rates of leprosy; vaccination for prevention of leprosy in other regions is not economically feasible except in areas with an extremely high incidence of the disease [74]. Development of an improved BCG vaccine, BCG booster, or alternate vaccine strain is an important research goal that could benefit control of both tuberculosis and leprosy. Skin test antigen studies and the identification of the appropriate protective M. leprae genomic DNA sequence could also lead to an improved vaccine for leprosy [75].

Prophylaxis — Outside endemic areas, no prophylactic treatment is recommended.

Within endemic areas, the World Health Organization (WHO) 2018 guidelines recommend prophylaxis (with single-dose rifampin [SDR]) for adults and children ≥2 years [6]. Several studies are underway to evaluate the benefit of this practice [76]. In a cluster-randomized controlled trial in Bangladesh including 28,092 contacts of 1037 patients with newly diagnosed leprosy, use of SDR in adults (600 mg) and children (300 mg) was associated with a reduction in number of new cases for a period of two years by 57 percent (confidence interval 33 to 72 percent) [77]. After this time, however, the number of new cases in treated and control populations was the same.

Neuritis (pain, burning or tingling, sudden numbness, or loss of function) must be treated aggressively to prevent or minimize nerve injury and subsequent deformity and disability. Neuritis is treated primarily with corticosteroids. Nerve function appears to improve after corticosteroid treatment in 60 to 70 percent of patients, but it may remain impaired in patients with pre-existing or recurrent neuritis [78]. About one-third of impaired nerves do not improve with corticosteroid treatment [79]. In a controlled trial of treatment for type 1 reactions with three different treatment regimens, the greatest improvement in nerve function occurred in the group receiving higher dose of prednisone (60 mg) and longer duration (20 weeks or longer) [42]. Treatment is best individualized; in some cases, even higher doses and longer duration of prednisone may be required. No long-term benefit has been associated with prophylactic corticosteroid treatment for prevention of neuritis [44]. (See 'Treatment of immunologic reactions' above.)

Elimination and control — In the early 1990s, the WHO and others promoted elimination of leprosy as a public health problem by the year 2000 [80]. Others have argued that leprosy is a poor choice for an elimination target given its long incubation time and other factors [81]. Moreover, 'elimination as a public health problem' has been confused with 'eradication,' leading to unrealistic expectations [82].

In 2000, the World Health Assembly declared that the goal of elimination of leprosy as a public health problem had been reached globally [83]. After this, many countries greatly reduced or eliminated their leprosy control programs. However, the annual number of newly diagnosed cases has remained steady since 2000, indicating that transmission has not been interrupted in many endemic areas [84]; in addition, it is likely that millions of cases have not been counted [84].

In 2018, a new Global Partnership for Zero Leprosy was inaugurated, incorporating nongovernmental organizations and other stakeholders [85]. The Partnership's approach is somewhat more nuanced, recognizing different specific goals for zero transmission, zero disability, and zero discrimination. However, the biological challenges of leprosy remain, including poor understanding of transmission. Even once disease elimination has been achieved, the implications for people with social, physical, or emotional sequelae must be addressed [86].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Leprosy".)

SUMMARY AND RECOMMENDATIONS

●Leprosy (also known Hansen's disease) is an infectious disease caused by Mycobacterium leprae that involves the skin and peripheral nerves. Leprosy is an important global health concern; early diagnosis and a full course of treatment are critical for preventing lifelong neuropathy and disability. (See 'Introduction' above.)

●Our approach to treatment of leprosy is as follows (see 'Selecting a regimen' above):

•For patients with tuberculoid disease, we suggest treatment with dapsone (100 mg daily) and rifampicin (600 mg daily) for duration 12 months (Grade 2C).

•For patients with lepromatous disease, we suggest treatment with dapsone, rifampicin, and clofazimine (50 mg daily) for duration 24 months (Grade 2C).

This approach is consistent with the United States National Hansen's Disease Program but differs from guidelines issued by the World Health Organization.

●Neuritis must be treated aggressively to try to prevent or minimize nerve injury and thus prevent deformity and disability. We suggest treatment of neuritis with corticosteroids (Grade 2C). (See 'Selecting a regimen' above.)

●While on treatment, routine follow-up visits should be scheduled every three months. Visits should consist of a clinical examination, including assessment of the skin, nerves, limbs, and eyes, as well as laboratory studies to assess drug toxicity. Patient education is important; disease progression during therapy is almost always due to poor adherence to treatment. (See 'Clinical response and follow-up' above.)

●Immunologic reactions are systemic inflammatory complications that occur before, during, or after treatment. In general, antimicrobial therapy should be continued in the setting of immunologic reactions, and patients should be reassured that the symptoms are not a reaction to the medications. Mild reactions without neuritis or ulceration can be managed with supportive care. For severe reactions with neuritis, we suggest prompt treatment with corticosteroids to avoid permanent nerve damage (Grade 2C). In such cases, rifampin administration should be reduced to once monthly. Second-line agents for treatment of immunologic reactions are discussed above. (See 'Treatment of immunologic reactions' above.)

●Control measures for leprosy include clinical management of active cases as well as contact management. Vaccination with Bacillus Calmette-Guérin is partially protective for leprosy. Development of an improved vaccine is an important research goal for prevention. (See 'Prevention' above.)