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 [1-3].

M. leprae and M. lepromatosis comprise "Mycobacterium leprae complex" [4]. The deoxyribonucleic acid (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 pathogens with a tropism for nerves) and cause the same clinical disease [5].

Leprosy is an important global health concern. Contrary to popular folklore, leprosy is not highly contagious, and effective treatment is available [1,6-8]. 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 [9].

Not all patients have access to appropriate therapy, and not all countries have the infrastructure to support leprosy control efforts [10]. Worldwide, the number of dedicated leprosy programs is declining, and international migration is bringing patients to nearly every region [11].

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'.)

ANTIMICROBIAL THERAPY

General approach — Treatment of leprosy consists of multidrug therapy (MDT) to minimize the likelihood of resistance [1]. First-line medications include dapsone, rifampin, and clofazimine. These agents are effective for treatment of leprosy due to M. leprae and M. lepromatosis [12-17].

No controlled trials comparing drug combination regimens have been performed; relapse rate is an important criterion for efficacy, and evaluation of relapse rate requires a long observation period (approximately 15 to 20 years). The efficacy of the individual agents had been demonstrated clinically, in animal studies, and in vitro [18-20].

Within the United States — Our treatment approach is in alignment with the United States National Hansen's Disease Program (NHDP), as follows (table 1 and table 2) [2]:

●Tuberculoid disease (TT, BT types; the WHO refers to this as paucibacillary [PB]) – Dapsone and rifampin for 12 months

●Lepromatous disease (BB, BL, LL types; the WHO refers to these as multibacillary [MB]) – Dapsone, rifampin, and clofazimine for 24 months

The NHDP approach follows World Health Organization (WHO) guidance issued in 1982 [7], which differs from the WHO 2018 guidelines with respect to the following:

●Duration of therapy – The NHDP (WHO 1982) approach consists of longer duration of therapy than the WHO 2018 approach; the NHDP has maintained a conservative approach in the absence of robust data to support shortened duration of treatment.

●Frequency of rifampin administration – The NHDP approach consists of more frequent rifampin administration (daily rather than monthly). This approach is supported by a study including 158 patients with leprosy (123 with MB disease) treated with regimens including daily rifampin and followed for 10 to 15 years; only one case of relapse was observed (in a patient with MB disease who was treated with a two-drug regimen rather than a three-drug regimen) [6]. While this relapse rate is similar to that of the WHO, the WHO rate is based on a shorter follow-up period (5 years).

●Role of clofazimine – The NHDP excludes clofazimine for treatment of PB disease. (See 'Outside the United States' below.)

In the United States, medication for the treatment of leprosy is provided free of charge by the NHDP (1-800-642-2477) [11].

Outside the United States — The 2018 WHO guidelines treatment approach is as follows (table 1 and table 2) [1]:

●Tuberculoid (TT-BT; PB) disease: Dapsone, rifampin, and clofazimine for 6 months.

●Lepromatous (BB-BL-LL; MB) disease: Dapsone, rifampin, and clofazimine for 12 months.

Compared with NHDP, use by the WHO of a shorter treatment duration and less frequent rifampin administration (monthly rather than daily) partly reflects cost considerations.

Use of clofazimine for patients with PB disease is controversial because treatment with dapsone and rifampin (without clofazimine) has been successful. However, it has been proposed that routine use of clofazimine reduces the likelihood of undertreating patients with MB disease who may be misclassified as having PB disease. In the United States, the classification of all cases includes histopathologic assessment of a skin biopsy, including documentation of the bacterial load, and misclassification is not an issue.  

The WHO distributes medications through the Ministry of Health in each country [21].

Clinical response and follow-up

●Clinical response – The exact time to noninfectiousness is not known since M. leprae cannot be cultivated; however, treatment likely renders the patient noninfectious within a few days.

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) [22]. 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 [23]. 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 [9]. Therefore, if adherence to the well-established MDT protocols is good, killing of the bacilli and resolution of the lesions can be expected.

●Follow-up – While on treatment, we schedule the first follow-up in two to four weeks to evaluate for side effects of medications. After that, we schedule routine follow-up visits 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 be asked about 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.

●Hand and foot care – 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.

●Eye care – Examination of the eyes should include assessment of lid closure, cornea, and conjunctiva [24]. Complex problems such as iridocyclitis should be managed by a specialist. Corneal anesthesia and lagophthalmos require protective measures and corrective surgery.

●Follow-up skin biopsies – If histopathologic follow-up evaluation is desired in lepromatous (MB) cases, we favor obtaining skin biopsies from the same lesion at one- to two-year intervals. The reduction of inflammation and the decline of bacilli in the tissues can be assessed. Processing and interpretation of biopsies for this purpose are available from the NHDP at no cost.

●Laboratory follow-up – 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 – After completion of treatment, annual follow-up for three more years is warranted for patients with tuberculoid disease, and annual follow-up 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.

Adverse effects of antimicrobial agents

●Dapsone – Dapsone is 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. (See "Methemoglobinemia" and "Drug-induced neutropenia and agranulocytosis" and "Drug-induced hemolytic anemia".)

Quantitative G6PD assays discriminate intermediate levels with greater accuracy than qualitative assays [25]. Qualitative tests can identify severe deficiencies but do not identify intermediate levels as effectively, and therefore, the results should be interpreted cautiously [25]. A normal result (absence of G6PD deficiency) for adults ranges 7 to 20.5 units/gram of hemoglobin and depends on gender, pregnancy status, biogenetics, and other factors [26].

Patients with severe deficiency (<10 percent normal) should not be treated with dapsone due to risk of severe hemolytic anemia. Patients with moderate deficiency (10 to 60 percent of normal range) may have intermittent hemolytic anemia if treated with dapsone; if dapsone must be used in such cases, close clinical monitoring with serial blood count measurements is warranted.

●Rifampin – Rifampin is the most bactericidal drug that is routinely used for the treatment of leprosy.

Rifampin toxicity correlates with the dose and the interval between doses. The standard doses for leprosy are relatively nontoxic; 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 human immunodeficiency virus (HIV) protease inhibitors, among many others. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

●Clofazimine – 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) [27].

Clofazimine 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 [28].

The major adverse effect of clofazimine is skin pigmentation (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 immunologic reactions may occasionally produce gastrointestinal side effects.

●Alternative agents – The following agents are bactericidal for M. leprae and may be used if the standard agents are contraindicated. However, they have not been evaluated in adequately powered clinical trials; they should be used in consultation with clinicians who experienced with treatment of leprosy.

•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.

Side effects of minocycline include teeth discoloration in children, occasional pigmentation of the skin and mucous membranes, gastrointestinal complaints, and central nervous system toxicity including dizziness and unsteadiness.

•Clarithromycin – Several macrolides have been evaluated for activity against M. leprae; clarithromycin is the only effective agent. Clarithromycin has potent bactericidal activity but is less bactericidal than rifampin. At a dose of 500 mg daily, 99 percent of M. leprae are killed in 28 days and 99.9 percent by 56 days [29].

Gastrointestinal irritation, nausea, vomiting, and diarrhea are the most common adverse effects, but they do not usually necessitate drug discontinuation

•Fluoroquinolones – Fluoroquinolones with activity against leprosy include ofloxacin, levofloxacin, and moxifloxacin. Adverse effects of fluoroquinolones are discussed separately. (See "Fluoroquinolones".)

-Ofloxacin – Ofloxacin has good antibacterial activity and is the most widely accepted fluoroquinolone for treatment of leprosy [28]. 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 – Moxifloxacin is also highly bactericidal against M. leprae; further study of rifampin and moxifloxacin as combination short-term therapy is needed [30,31].

IMMUNOLOGIC REACTIONS AND NEURITIS

Immunologic reactions

General principles

●Clinical manifestations – 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 [32]. Clinical manifestations may include fatigue, malaise, fever, neuritis (nerve enlargement, tenderness, or loss of function), arthritis, iritis, and nasopharyngeal symptoms. The associated inflammation 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'.)

●Distinguishing immunologic reactions from other entities – For patients on appropriate antimicrobial therapy, the most common cause of disease progression is inadequate adherence. Other less common considerations include relapse or drug resistance. (See 'New skin lesions during or after treatment' below.)

●Continuation of antimicrobial therapy – 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.

Type 1 reaction (T1R, reversal reaction) — T1R typically occurs in patients with borderline tuberculoid (BT), mid-borderline (BB), or borderline lepromatous (BL) disease. Clinical manifestations of T1R are described separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Type 1 reaction (T1R, reversal reaction)'.)

●Mild reactions – Mild reactions (edema and erythema of existing skin lesions, in the absence of neuritis [nerve enlargement, tenderness, or loss of function] or skin ulceration) may be managed with analgesics such as nonsteroidal anti-inflammatory drugs [11]. Such patients must be observed closely for deterioration of nerve function, which requires more aggressive treatment.

●Severe reactions – Severe reactions (including neuritis [nerve enlargement, tenderness, or loss of function], skin ulceration, fever, and/or joint pain) warrant prompt treatment to avoid permanent nerve damage [33]. The mainstay of treatment consists of corticosteroids; potential alternative agents include cyclosporine and methotrexate.

•Corticosteroids

-Clinical approach – There is no consensus on the optimal dose or duration of corticosteroids for treatment of immunologic reactions [34]. Our approach consists of prednisone 40 to 60 mg daily (maximum 1 mg/kg); the duration is typically at least 12 weeks (or longer, depending on individual circumstances) followed by a taper, depending on the severity of the reaction and the response to treatment. Rapid improvement of nerve function occurs most often in situations when the lesion is of recent onset (less than six months).

-Rifampin dose adjustment – Coadministration of rifampin with prednisone accelerates metabolism of prednisone; for patients receiving prednisone, we reduce the rifampin dose from 600 mg daily to 600 mg monthly. After prednisone has been discontinued, daily rifampin should be resumed.

-Efficacy – The benefit of steroids is uncertain. In a 2016 review [35], moderate-quality evidence from two randomized trials including 179 patients with longstanding or mild nerve function impairment demonstrated no superior effect of corticosteroids over placebo with respect to nerve function improvement; however, a third trial including 334 patients with T1R demonstrated benefit from a 20-week steroid regimen over a 12-week regimen; at the end of 12 months, additional steroid treatment was required more frequently among patients who received the shorter course (46 versus 31 percent) [36]. In a subsequent randomized trial including more than 800 patients with leprosy and nerve function impairment, the efficacy of a 20-week prednisone course was comparable to that of a 32-week course for improving or restoring nerve function (78 percent) [37].

-Adverse effects – Prolonged use of corticosteroids entails the risk of many serious side effects. If prolonged therapy will be needed, switching to an every-other-day schedule may reduce the risk of side effects [38]. For patients receiving ≥20 mg of prednisone daily for one month or longer, initiation of prophylaxis for prevention of Pneumocystis warrants consideration. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis' and "Major adverse effects of systemic glucocorticoids".)

-No role for prophylaxis – No long-term benefit has been associated with prophylactic corticosteroid treatment for prevention nerve function impairment.

In a randomized trial including 636 patients with newly diagnosed multibacillary (MB) leprosy, patients were randomly assigned to receive antimicrobial therapy with or without prednisolone (20 mg/day for three months, followed by taper). Those who did not receive prednisone had a higher likelihood of nerve function impairment at four months (15 versus 4 percent; relative risk 3.9, 95% CI 2.1 to 7.3); however, the benefit was not maintained at one year (relative risk 1.3, 0.9 to 1.8) [39].

•Other agents

-Cyclosporine – Cyclosporine may be a useful second-line treatment for severe T1R in patients who do not respond to or who are unable to take corticosteroids [40]. It has been demonstrated to improve sensory nerve impairment and skin lesions in small numbers of patients in Brazil, Ethiopia, and Nepal [41,42]. Further study is needed to determine optimal dosing and to compare efficacy and toxicity with corticosteroids.

-Methotrexate – In patients with concomitant diabetes, methotrexate is a potential steroid sparing regimen; further study is needed [43].

Type 2 reaction (T2R, erythema nodosum leprosum [ENL]) — T2R occurs in patients with BL and lepromatous (LL) disease. Clinical manifestations of T2R are described separately. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Type 2 reaction (T2R, erythema nodosum leprosum, ENL)'.)

●Mild reactions – Mild reactions (low-grade fever, mild skin lesions, mild nerve pain without loss of function) may be managed with analgesics such as nonsteroidal anti-inflammatory drugs [11].

●Severe reactions – Severe reactions (including fever, neuritis [nerve pain, tenderness, or loss nerve function], skin ulceration, loss of sensation or muscle weakness [hands, feet, or eyes], joint pain, eye pain and redness [uveitis, scleritis], and/or headache) warrant prompt treatment to avoid permanent nerve damage.

The mainstay of T2R treatment consists of corticosteroids; in addition, thalidomide is a favored drug for treatment of T2R in areas where available. Alternative approaches include methotrexate, clofazimine, or tumor necrosis factor-alpha (TNF-a) inhibitors.

•Use of corticosteroids – Use corticosteroids for treatment of T2R is as discussed above for T1R. (See 'Type 1 reaction (T1R, reversal reaction)' above.)

•Other agents – Other immunosuppressive drugs have been evaluated for management of T2Rs [40].

-Thalidomide – Thalidomide is a favored drug for treatment of T2R in areas where available [34], but teratogenicity limits its use in women of childbearing age. Thalidomide is typically used for situations in which prednisone is not effective for controlling the reaction or in which use of prednisone is precluded by adverse effects. There has been no rigorous comparison of clinical efficacy between thalidomide and prednisone; in one study including 30 patients with erythema nodosum leprosum (ENL), thalidomide enabled weaning off of steroids over a median of two months in 75 percent of cases [44].

Our approach consists of initial treatment with 200 to 400 mg daily; frequently, this regimen controls the reaction within 48 hours. Subsequently, we taper the dose to a maintenance level, generally around 100 mg daily. Thalidomide may be continued for several years to control ENL; every few months, we attempt to taper off the drug. In our experience, a few patients with severe, prolonged T2Rs have continued use of thalidomide for up to 10 years.

Development of symmetrical painful paresthesia of the hands and feet and sensory loss in lower extremities should prompt discontinuation of thalidomide.

In a retrospective review including 102 patients with ENL treated with thalidomide, improvement was observed in 67 percent of cases; recurrence occurred in 16 percent with a mean duration of 14 months [45].

In the United States, 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 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.

-Methotrexate – For patients with ENL and neuropathy (loss of protective sensation in at least one limb) who are unable to tolerate high-dose steroids, methotrexate (10 to 25 mg weekly) with or without low-dose corticosteroids (1 to 7.5 mg daily) is a potential alternative regimen [43,46,47]. The duration of treatment may range from 12 to 24 months, guided by individual status of the peripheral neuropathy. Further study of methotrexate for management of leprosy reactions is ongoing [48].

Patients treated with methotrexate should have baseline laboratory testing and receive coadministration of folate; these issues are discussed separately. (See "Therapeutic use and toxicity of high-dose methotrexate" and "Major side effects of low-dose methotrexate", section on 'Prevention of side effects with folate'.)

-Clofazimine – Clofazimine is not useful for the management of acute T2R but may be used as an alternative regimen for chronic T2R in patients who are unable to be treated with high-dose corticosteroids [49].

Clofazimine may be 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 MB regimen may have some protective effect in preventing reactions since T2R appears to have become less common with inclusion of this agent in treatment regimen.

In the United States clofazimine can be obtained through the National Hansen's Disease Program (NHDP; phone 1-800-642-2477).

-TNF-a inhibitors – In the most intractable cases, anti-TNF agents have been employed [50], but this is advisable only after the patient has completed a full course of multidrug therapy (MDT).

Successful use of TNF-a inhibitors 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 [51]. In addition, we are aware of unpublished cases in which use of these agents was not successful for management of T2R [52].

Lucio phenomenon — Lucio phenomenon (necrotizing vasculopathy in patients with longstanding untreated lepromatous leprosy) is a rare but severe and potentially life-threatening reaction. Management requires antimicrobial therapy and corticosteroids as well as skin and wound care comparable with that given for extensive burns [53]. Such patients should be managed in consultation with a clinician experienced with the treatment of Lucio reactions.

Neuritis — Some patients have progressive sensory or motor loss in hands or feet in the absence of nerve pain or other signs of immunologic reaction. For patients with deteriorating nerve function for less than six months who are adherent to antimicrobial treatment, we favor treatment with corticosteroids. The approach is as discussed above for treatment of immunologic reactions. (See 'Type 1 reaction (T1R, reversal reaction)' above.)

Neuritis may persist for months or years; there are no rigorous data on its responsiveness to treatment [32].

OTHER MANAGEMENT ISSUES

New skin lesions during or after treatment — The development of new lesions during or after completion of treatment is usually attributable to an immunologic reaction (see 'Immunologic reactions and neuritis' above); less common causes include disease relapse and drug resistance. (See 'Relapse' below and 'Drug resistance' below.)

During treatment, baseline skin lesions may remain unchanged or appear to worsen, with erythema and swelling. Development of new skin lesions almost always reflects an immunologic reaction.

Clinical approach — The characteristic clinical features are usually sufficient to make the diagnosis of an immunologic reaction. If there is uncertainty about the diagnosis, a biopsy may be helpful. Polymorphonuclear leukocytes are a hallmark of type 2 reactions (T2Rs); no reliable histologic criteria have been identified for type 1 reactions (T1Rs), so this remains a clinical diagnosis. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Skin biopsy'.)

If the new lesion is consistent with an immunologic reaction, we typically begin with a prednisone challenge (20 to 60 mg/day for seven days), followed by reassessment [3]; for patients who respond clinically, we continue treatment with methotrexate (as a steroid-sparing agent) for six months.

If a relapse is suspected, a biopsy should be obtained; in addition, polymerase chain reaction (PCR) of biopsy tissue may be performed for detection of mutations associated with drug resistance.

Relapse — Most relapses occur 5 to 10 years or more after completion of treatment [54]. The World Health Organization (WHO) estimated relapse rates at nine years following multidrug therapy for multibacillary (MB) and paucibacillary (PB) leprosy are 0.77 and 1.07 percent, respectively [34]. Risk factors for relapse include incomplete treatment and very high bacterial load at the onset of treatment [55].

●Diagnosis – If a relapse is suspected, a biopsy should be obtained. During treatment, the tissue bacterial load falls to zero slowly (over a period of years). The bacterial load in a biopsy or skin smear may be expressed as a 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) [56]. In relapse, the BI rises again. An increase in from 0 to 2 or more indicates probable relapse [57].

●Management – The optimal approach to treatment of relapse is uncertain. In general, treatment consists of restarting the same regimen used for initial therapy [57]. Patients who presented initially with PB disease but relapse with MB leprosy should be retreated with a 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. For patients with lack of clinical response, or relapse, testing for mutations can be done from paraffin-embedded tissues obtained prior to treatment and at the time of suspected relapse or resistance.

Drug resistance — Drug resistance in leprosy is relatively uncommon [58]. In a WHO surveillance study that evaluated the rate of M. leprae antimicrobial resistance among more than 1900 patients in 19 countries between 2009 and 2015, the overall rates of resistance were: rifampin (3.8 percent), dapsone (5.3 percent), and ofloxacin (1.3 percent) [59]. The rate of rifampin resistance in new cases was 2 percent and in relapsed cases was 5 percent. The rate of rifampin resistance was highest among new cases in Brazil and India (15 and 8 percent, respectively) and among relapsed cases in Colombia and Mozambique (24 and 20 percent, respectively).

●Diagnosis – For patients who do not respond to treatment for an immunologic reaction (with prednisone challenge), we pursue biopsy with PCR to evaluate for mutations associated with drug resistance.

In the United States, the Molecular Biology Laboratory of the National Hansen's Disease Program (NHDP) provides testing for drug resistance mutations on all biopsies received. In other settings, if clinical and laboratory evidence suggest relapse, testing for drug resistance should be performed on a biopsy of the new lesion in order to determine appropriate agents for retreatment [11].

●Management – Alternative agents for treatment of leprosy include minocycline, clarithromycin, and fluoroquinolones (ofloxacin, levofloxacin, and moxifloxacin); their use for treatment of leprosy has not been evaluated in controlled trials.

We are in agreement with the WHO guidelines for treatment of drug-resistant leprosy, as follows (table 4) [1,3]:

•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.

Patients with HIV infection — 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 [60-62]. (See "Immune reconstitution inflammatory syndrome".)

The response to leprosy treatment in individuals with HIV infection appears to be comparable with the response in individuals without HIV infection [62].

Pregnant patients — Immunologic reactions occur more frequently in pregnant and postpartum patients than in nonpregnant patients [63-65]. In two small series, such reactions were observed in up to 38 percent of patients [66,67]. T2Rs 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 'Antimicrobial therapy' 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 skin or neurologic manifestations develop.

●Prophylaxis

•Household contacts – Leprosy household contacts are generally defined as persons living in the same dwelling or sharing the same kitchen as the index case. These include family members but also domestic staff, aids, co-workers, or others sharing the same accommodation. A family member living elsewhere should not be considered as a contact [68-70]. In some studies a household contact has been defined more precisely as a person living in the same house as a patient with leprosy for a cumulative total of at least six months, within the period from six years before diagnosis to one month after initiation of multidrug therapy in the patient [68,69].

For household contacts of patients with leprosy, we favor postexposure prophylaxis with rifapentine; dosing is outlined in the table (table 5). For household contacts <10 years of age, we monitor clinically for signs of M. leprae infection.  

This approach is supported by a cluster-randomized trial including 7450 household contacts (≥10 years of age) of patients with newly diagnosed leprosy in China treated with rifapentine (single dose), rifampin (single dose), or no intervention, the incidence (intention-to-treat analysis) of new leprosy cases over four-year follow-up was lower in the rifapentine group than the control group (0.09 versus 0.55 percent; incidence ratio 0.16, multiplicity-adjusted 95% CI 0.03-0.87); the cumulative incidence did not differ significantly between the rifampin group and the control group [68]. The benefit of rifapentine was observed through all four years of follow-up.

•Social contacts – A social contact is defined by the WHO as an individual who has been exposed to a patient with infectious leprosy for at least 20 hours per week for at least three months per year; this may include neighbors and associates at work or school [70].

For social contacts of patients with leprosy, we are in agreement with the WHO recommendation to use a single dose of rifampin for adults and children ≥2 years of age (table 5) [1]. For children <2 years of age, we monitor clinically for signs of M. leprae infection.

This approach was evaluated in a cluster-randomized controlled trial including more than 28,000 contacts of 1037 patients with newly diagnosed leprosy in Bangladesh treated with single-dose rifampicin or placebo; the protective effect was 57 percent (95% CI 33-72 percent) and lasted only for two years [71]. However, the least benefit was observed among household contacts (the participants at highest risk).

●Vaccination – 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].

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

●General principles – Leprosy (also known Hansen's disease) is an infectious disease caused by Mycobacterium leprae that involves the skin and peripheral nerves. Classification is summarized in the table (figure 1). Leprosy is an important global health concern; early diagnosis and treatment are important for preventing neuropathy and disability. (See 'Introduction' above and 'Classification' above.)

●Treatment approach

•Within the United States – Within the United States, our approach to treatment of leprosy aligns with the United States National Hansen's Disease Program (NHDP), as follows (table 1 and table 2) (see 'Within the United States' above):

-For patients with tuberculoid (paucibacillary [PB]; TT, BT) disease, we suggest treatment with dapsone and rifampicin for 12 months (Grade 2C).

-For patients with lepromatous (multibacillary [MB]; LL, BL, BB) disease, we suggest treatment with dapsone, rifampicin, and clofazimine for 24 months (Grade 2C).

•Outside the United States – Outside the United States, we are in agreement with the 2018 World Health Organization (WHO) approach, as follows (table 1 and table 2) (see 'Outside the United States' above):

-For patients with tuberculoid (PB; TT, BT) disease, we suggest treatment with dapsone, rifampin, and clofazimine for 6 months (Grade 2C).

-For patients with lepromatous (MB; LL, BL, BB) disease, we suggest treatment with dapsone, rifampin, and clofazimine for 12 months (Grade 2C).

Use of a shorter treatment duration and less frequent rifampin administration partly reflects cost considerations. In addition, it has been proposed that routine use of clofazimine reduces the likelihood of undertreating patients with MB disease who may be misclassified as having PB disease.

●Monitoring and follow up – During antimicrobial treatment, we schedule routine follow up every three months. Visits should include clinical examination (including assessment of the skin, nerves, limbs, and eyes) as well as laboratory studies to evaluate for drug toxicity. Patient education is important; disease progression during treatment is almost always due to poor adherence. (See 'Clinical response and follow-up' above.)

●Immunologic reactions – Immunologic reactions are systemic inflammatory complications that occur before, during, or after antimicrobial treatment of leprosy. (See 'Immunologic reactions' above.)

•Clinical approach – Mild reactions without neuritis or skin ulceration can be managed with supportive care. For patients with severe reactions with neuritis, we suggest treatment with prednisone (Grade 2C); the optimal dose and duration are uncertain and should be individualized. In addition, in regions where available, thalidomide is a favored drug for treatment of type 2 reaction (T2R), but teratogenicity limits its use in women of childbearing age. Other agents for treatment of immunologic agents are discussed above.

•Continuation of antimicrobial therapy – 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. During prednisone administration, rifampin should be administered once monthly.

●Neuritis – For patients with deteriorating nerve function for less than six months who are adherent to antimicrobial treatment, we suggest treatment with corticosteroids (Grade 2C); the optimal dose and duration are uncertain and should be individualized. (See 'Neuritis' above.)

●New skin lesions during or after treatment – The development of new lesions during or after completion of treatment is usually attributable to an immunologic reaction; less common causes include disease relapse and drug resistance. If there is uncertainty about the diagnosis, a biopsy is useful for diagnosis of T2R as well as detection of drug resistance mutations. For patients with a suspected immunologic reaction, we suggest a trial of steroids (Grade 2C). For patients with relapse, management consists of retreatment with multidrug therapy (MDT; substituting alternative drugs for any of those to which resistance has been identified). (See 'New skin lesions during or after treatment' above.)

●Prevention

•Prophylaxis – For household contacts of patients with leprosy, we suggest postexposure prophylaxis with rifapentine (Grade 2C); rifampin may be used as an alternative agent (table 5). Prophylaxis is also appropriate for social contacts. Contacts who are not treated should be monitored for signs of infection. (See 'Prevention' above.)

•Vaccination – Vaccination with Bacillus Calmette-Guérin (BCG) is partially protective for leprosy. (See 'Prevention' above.)