Leprosy

62 

Leprosy Diana N. J. Lockwood, Saba Lambert

KEY FEATURES • Leprosy, also known as Hansen’s disease, is a chronic granulomatous bacterial infection principally affecting skin and peripheral nerves. It is caused by Mycobacterium leprae. • After contact with an infective dose of M. leprae, most people will develop adequate protective immunity. Only a small percentage of individuals will develop clinical disease. Patients can present with manifestations that represent a spectrum of disease and host–pathogen interactions, ranging from heavy and diffuse organism loads and minimal host reactions, to pauci-bacillary disease and prominent host immune responses. • A patient with Hansen’s disease may present with a macular hypo-pigmented skin lesion, weakness or pain in the hand because of nerve involvement, facial palsy, acute foot drop, or a painless burn or ulcer in an anesthetic hand or foot. Patients may also present with painful eyes as a first indication of lepromatous leprosy. The diagnosis of leprosy should be considered in anyone from an endemic area who presents with typical skin lesions, neuropathic ulcers, or a peripheral neuropathy (sensory loss and/or weakness). • Diagnosis is usually based on clinical recognition and/or detection of acid-fast bacilli (AFB) in skin smears/ biopsies. • Treatment is based on the World Health Organization (WHO) multi-drug therapy (MDT) regimens and involves months of treatment. • Leprosy may be complicated by immunologic phenomena called reactions. These sudden episodes of acute inflammation are a medical emergency and occur in approximately 30% of leprosy patients. The inflammation is a result of immune reactions against M. leprae antigens. These immunologic reactions cause neurologic damage that leads to subsequent tissue damage and eventual deformity. Treatment often involves steroids. • Physiotherapy, education, early wound care, and behavioral modifications to minimize risk of trauma are important components of the long-term care of individuals with complications of leprosy.

THE CAUSATIVE ORGANISM AND HOST RESPONSE Mycobacterium leprae is an acid-fast, rod-shaped, gram-positive organism. It is an obligate intracellular pathogen, and it has not been grown in axenic medium since being identified as the causative organism of leprosy by Armauer Hansen in 1874. It can be harvested after prolonged incubation in the mouse footpad and occurs by natural infection in the nine-banded armadillo, which is a reservoir for the organism in the states of Texas and Louisiana in the United States, where transmission on M. leprae from armadillo to human has been recorded. In 2001, the genome of M. leprae was sequenced. The organism appears to have undergone extensive reductive evolution with considerable downsizing of its genome compared with M. tuberculosis. Almost half of the genome is occupied by pseudogenes.3 Transmission is thought to occur mainly through aerosolized nasal droplets, spread when coughing or sneezing takes place. Forty-eight percent of lepromatous patients compared with 3% of borderline patients have nasal discharge containing M. leprae. The number of acid-fast bacilli (AFB) in a single nasal blow averaged 1.1 × 108 in a study of 17 patients.4 Contacts of leprosy patients are at higher risk of developing the disease than the general population. There are case reports of leprosy occurring after presumed inoculation through the skin during surgical procedures, tattooing, or accidental trauma.5 The organism can persist outside the body under various environmental conditions for up to 5 months.6 After contact with an infective dose of M. leprae, most people will develop adequate protective immunity (Fig. 62.2). Only a small percentage of individuals will develop clinical disease. Infecting organisms are taken up by histiocytes in the skin and by Schwann cells in the peripheral nerves. This usually elicits an inflammatory response of histiocytes and lymphocytes. The earliest clinical sign is a vague, small, hypo-pigmented macule, described as indeterminate leprosy; over 70% of these heal spontaneously. If bacillary growth outstrips the defense mechanism, then the condition progresses to one of the patterns that make up the spectrum of disease in leprosy. The incubation period can range between 2 and 12 years. Inflammation plays an important role in the neurologic damage that leads to subsequent tissue damage and eventual deformity.

DIAGNOSIS OF LEPROSY The basis of a clinical diagnosis of leprosy is the presence of one of the three cardinal signs: • Hypo-pigmented/reddish skin lesions with possible sensory loss • Thickened peripheral nerves • AFB seen in skin smears/biopsies

Leprosy, also known as Hansen’s disease, is a chronic granulomatous bacterial infection principally affecting skin and peripheral nerves.1 In 2016, 214,783 new cases were registered worldwide and reported to the World Health Organization (WHO). The top six endemic countries are India, Brazil, Indonesia, Ethiopia, Democratic Republic of Congo, and Nepal.2 Most new cases occur in resourcepoor countries, and leprosy continues to be a significant public health problem and a stigmatizing disease (Fig. 62.1).

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A patient may present with a macular hypo-pigmented skin lesion (Fig. 62.3), weakness or pain in the hand due to nerve involvement, facial palsy, acute foot drop, or a painless burn or ulcer in an anesthetic hand or foot. Patients may also present with painful eyes as a first indication of lepromatous leprosy. The diagnosis of leprosy should be considered in anyone from an endemic area who presents with typical skin lesions, neuropathic ulcers, or a peripheral neuropathy (sensory loss and/or weakness).

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CHAPTER 62 Leprosy



Geographic distribution of new leprosy cases 2016

62

Total new cases detected 0 1–99 100–999 1000–9999 0

>10000

1,500 3,000

6,000 Kilometers

Not reported Fig. 62.1  Global leprosy new cases map, 2016. (Courtesy of WHO.)

No disease

Infection with M. leprae

Indeterminate leprosy, Hypopigmented patch, Can heal or lead to disease spectrum:

Ridley-Jopling classification

TT

BT

BB

BL

LL

WHO classification

PB

PB/MB

MB

MB

MB

Bacterial index

0-1

0-2

2-3

1-4

4-6

Fig. 62.2  Relationship between M. leprae infection and clinical leprosy.

Laboratory Tests

CLASSIFICATION OF LEPROSY

The presence of AFB in skin smear examination or biopsy material examination can provide supporting evidence for the diagnosis. The Bacterial Index gives a measure of bacterial density in the skin sample under examination on a logarithmic scale ranging from 0 to 6. Histopathologic evaluation is essential for accurate classification of leprosy lesions and is the best diagnostic test in a well-resourced setting, both for confirming and excluding the diagnosis of leprosy. Recent advances have been made in serologic diagnostic tests. Antibodies to the M. leprae–specific antiphenolic glycolipid (PGL-1) are present in 90% of patients with untreated lepromatous disease, but only 40% to 50% of patients with paucibacillary disease and 1% to 5% of healthy controls.7 An immunohistochromatographic assay, the ML flow test, based on PGL-1 detection, has been used in Brazil.8 The drawback with serologic tests is that they do not detect patients with pauci-bacillary leprosy. Polymerase chain reaction (PCR) for detection of M. leprae– encoding specific genes or repeat sequences is potentially highly sensitive and specific, as it detects M. leprae DNA in 95% of multi-bacillary and 55% of pauci-bacillary patients. PCR is currently not used in clinical practice.7

Leprosy may be considered an immunologic disease. Immunity defines susceptibility to leprosy, type of clinical leprosy, pathology, and major clinical complications of leprosy. Classification of the disease is important to determine prognosis, patients at higher risk of reactions, and nerve damage, as well as select appropriate treatment. Leprosy patients can be classified using two systems: the Ridley–Jopling system and the WHO system. The Ridley–Jopling system9 (Fig. 62.4) uses clinical and histopathologic features and the Bacterial Index. Leprosy manifests in a spectrum of disease forms, ranging from the tuberculoid to the lepromatous. The clinical manifestations of leprosy are determined by the host’s response to the leprosy bacillus: tuberculoid (TT) patients have a strong cell-mediated immune response manifesting as limited clinical disease, granuloma formation, and no detectable mycobacteria; lepromatous (LL) patients have no cell-mediated immunity to M. leprae and have widespread disease and a high bacterial load. Between these two extremes there is a range of variations in host response—these comprise borderline cases (BT, borderline tuberculoid; BB, borderline borderline; BL, borderline lepromatous). Immunologically, borderline cases are

560

PART 3  Bacterial Infections

Fig. 62.3  Young patient with extensive leprosy patches (BT) that are hypo-pigmented, dry, hairless, and anesthetic. There are several lesions with a well-defined but irregular edge; a few satellite lesions are visible.

Fig. 62.5  A 25-year-old man with lepromatous leprosy. The skin is heavily infiltrated and multiple nodules are present, giving a leonine appearance. Partial madarosis and nodules on the ears are present.

those with six or more lesions (Fig. 62.5) are classified as multibacillary. This is a quick and useful tool that can be employed by a wide variety of health care workers, as it provides a low-cost strategy for leprosy diagnosis, without the need for skilled neurologic assessment and slit skin smear examination.

CLINICAL FEATURES The cardinal signs of leprosy are anesthetic skin lesions, numbness or weakness as a result of damage to sensory and motor nerves, and ulcers or burns in an anesthetic hand or foot. However, the clinical presentation ultimately depends on the host’s immunity to M. leprae, and clinical features can be divided into the disease spectrum classified according to Ridley–Jopling (Table 62.1).

TREATMENT

Fig. 62.4  The Ridley–Jopling classification and the relationship with host immunity.

unstable, and polar tuberculoid and lepromatous cases are stable. Patients can move along the spectrum in the absence or presence of treatment. The WHO classification is a simplified version that can be used in the field when slit skin smears are not available. Patients with fewer than six lesions are classified as pauci-bacillary, and

The management of leprosy consists of treating the M. leprae infection with antibiotic chemotherapy, managing the immunemediated reactions (discussed separately), preventing nerve damage, and educating the patient. Antibiotic chemotherapy is based on the WHO multi-drug therapy (MDT) regimens (Table 62.2). Treatment response is assessed by clinical improvement of skin lesions and a fall in the Bacterial Index. The regimens are highly effective with very low relapse rates and no multi-drug resistance. Over the past 20 years, more than 15 million people have received MDT and have been cured of M. leprae infection. Relapse rates after treatment with MDT vary from 0% to 2.5% in paucibacillary disease. In multi-bacillary disease, the published rates of relapse are between 0% and 7.7%. The study with the highest relapse rate in multi-bacillary patients demonstrated that 90%

CHAPTER 62 Leprosy



561

TABLE 62.1  Major Clinical Features of the Disease Spectrum in Leprosy Classification Ridley–Jopling

WHO

Indeterminate

PB

True Tuberculoid (TT)

Bacterial Index

62

Skin Lesions

Nerve Involvement

Systemic Features

0

Solitary hypo-pigmented 2–5 cm lesion. May become TT-like.

None clinically detectable.

Nil

PB/MB

0–1

Few, often one macule or plaque with well-defined border and sensory loss. The patch is dry (loss of sweating) and hairless.

May have one peripheral nerve enlarged. Occasionally presents as a mono-neuropathy.

Nil

Borderline tuberculoid (BT)

MB

0–2

Several larger irregular plaques with partially raised edges. Satellite lesions at the edges.

Asymmetric multiple nerve involvement.

Nil

Borderline Borderline (BB)

MB

2–3

Many macular lesions and infiltrated lesions with punched-out centers.

Asymmetric multiple nerve involvement.

Nil

Borderline lepromatous (BL)

MB

1–4

Many small macular lesions and multiple nodules and papules

Widespread nerve thickening. Sensory and motor loss.

Some of features listed later

Lepromatous lepromatous (LL)

MB

4–6

Numerous nodular skin lesions in a symmetric distribution, not dry or anesthetic. May present as many confluent macular lesions. There are often thickened shiny earlobes, loss of eyebrows, and diffuse skin thickening.

Widespread nerve enlargement. Glove and stocking anesthesia occurs late in disease.

Nasal stuffiness, epistaxis. Testicular atrophy. Ocular involvement. Bones and internal organs can be affected.

MB, Multi-bacillary; PB, pauci-bacillary.

TABLE 62.2  World Health Organization–Recommended Multi-Drug Therapy Regimens for Adults Drug Treatment

TABLE 62.3  Centers for Disease Control and Prevention– Recommended Multi-Drug Therapy Regimens for Adults in the United States

Type of Leprosy

Monthly Supervised

Daily, SelfAdministered

Duration of Treatment

Type of Leprosy

Drug Treatment Daily, Self-Administered

Duration of Treatment

Pauci-bacillary (TT and BT)

Rifampin 600 mg

Dapsone 100 mg

6 mo

Pauci-bacillary (TT and BT)

Rifampin 600 mg and dapsone 100 mg

12 mo

Multi-bacillary (BB,BL and LL)

Rifampin 600 mg, Clofazimine 300 mg

Clofazimine 50 mg Dapsone 100 mg

12 mo

Multi-bacillary (BB, BL, and LL)

Rifampin 600 mg, dapsone 100 mg, and clofazimine 50 mg

24 mo

BB, Borderline borderline; BL, borderline lepromatous; BT, borderline tuberculoid; LL, lepromatous lepromatous; TT, true tuberculoid.

BB, Borderline borderline; BL, borderline lepromatous; BT, borderline tuberculoid; LL, lepromatous lepromatous; TT, true tuberculoid. TABLE 62.4  Side Effects of Multi-Drug Therapy Drugs

of relapses occurred in patients who had an initial Bacterial Index of >4.10 Relapse can occur 5 to 15 years after treatment. Two recent big trials have tested a 6-month-only regimen known as UMDT (Uniform MDT) consisting of rifampin, dapsone, and clofazimine for all patients. Relapse rates were as low as 1%.11,12 Children with leprosy can be treated with the same regimen, but medication dosage needs to be weight adjusted. Consultation with a specialist is recommended. In the United States, treatment regimens vary from the WHO-MDT (Table 62.3). The more common side effects of the WHO-MDT drugs are summarized in Table 62.4. Adverse effects due to dapsone are common and sometimes fatal. Patients should have their hemoglobin checked monthly for the first 3 months while taking dapsone.13 Skin pigmentation with clofazimine often causes patients with pale skins to request non–clofazimine-containing regimens.

Alternative Antimicrobial Agents Minocycline 100 mg daily, clarithromycin 500 mg daily and ofloxacin 400 mg daily are all effective against M. leprae, and can be used as a substitute for clofazimine or dapsone in a multi-drug regimen. These drugs can also be used in single monthly dose combinations.14

Drug

Side Effect

Dapsone

Hemolytic anemia Exfoliative dermatitis Fixed drug eruption Psychosis

Clofazimine

Severe dryness of skin Brownish or reddish discoloration of skin and patch Abdominal pain—sign of acute abdomen Pigmentation of conjunctiva

Rifampin

Flulike syndromes (dose-dependent hypersensitivity reaction) Liver dysfunction Abdominal pain Loss of appetite Red urine, stool, saliva

REACTIONS Leprosy is complicated by immunologic phenomena called reactions. These sudden episodes of acute inflammation are a medical emergency and occur in approximately 30% of leprosy patients. The inflammation is caused by immune reactions against M. leprae antigens. Patients can present in reaction before MDT treatment, and a significant proportion of patients develop reactions within

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PART 3  Bacterial Infections

the first 6 months of treatment. However, reactions can also occur after successful MDT treatment and are probably caused by the persistence of M. leprae antigens. Patients may experience repeated reactions after treatment, resulting in increased suffering and disability. There is also an increase in the incidence of reactions in postpartum patients. These immunologic reactions and the influx of inflammatory cells cause nerve damage through demyelination. It is this neurologic damage that leads to subsequent tissue damage and eventual deformity (Fig. 62.6). The early recognition of reactions is important to minimize nerve damage. Reactions place a significant burden on leprosy services. Reactions require treatment with immune-modulatory drugs. High doses of these agents for prolonged periods are often required, and this may contribute to morbidity. Physicians must be aware of the complications of immune suppression as well as the potential drug interactions between drugs used to treat reactions and components of MDT. Patients prescribed oral corticosteroids should be prescribed a gastric acid suppression agent—preferably a proton pump inhibitor. The need for corticosteroid-induced osteoporosis prevention therapy should be assessed in each individual. Two distinct types of leprosy reaction occur: leprosy type 1 reactions (T1Rs, also known as reversal reactions) and type 2 reactions (also known as erythema nodosum leprosum [ENL]).

Management of Type 1 Reactions The clinical manifestations of these reactions are edema and erythema of skin lesions and neuritis. Acute neuritis (defined as spontaneous nerve pain, paresthesia, or tenderness with new sensory or motor impairment of recent onset) may also occur without evidence of skin inflammation (Fig. 62.7). Corticosteroids are used to treat moderate and severe reactions, where pain is severe and nerve function impairment (NFI) is present. Prednisolone 40 to 60 mg daily should be started and tapered down after clinical improvement to the minimal effective dose until the reaction subsides. There is no clear consensus on the optimum dose of corticosteroids or the length of treatment, although a recent study has shown that a longer period of treatment (5 months) was more beneficial than the 3 months often used15 (Table 62.5). Other agents have been compared with prednisolone in the management of T1Rs. Cyclosporine at a starting dose of 7.5 mg/kg/day showed promise in a randomized study of 73 individuals conducted in

Fig. 62.6  Median and ulnar nerve damage in leprosy: dry skin, muscle wasting, mobile clawing of fourth and fifth fingers, desensitization, and painless burn on the fourth finger.

TABLE 62.5  Comparison of Clinical Features of Type 1 and Type 2 Leprosy Reactions Parameter

Type 1

Type 2 (ENL)

Patients at risk

BL, BB, BT

LL, BL

Onset of reaction

Gradual, over a few weeks

Sudden, “overnight”

Cutaneous lesions

Increased erythema and induration of previously existing or new lesions

Numerous erythematous, tender nodules on face, extremities, or trunk without relationship to prior lesions

Neuritis

Frequent, often severe

Frequent, often severe

Systemic symptoms

Afebrile, mild malaise

Fever, malaise, lymph node enlargement, arthritis, iritis, orchitis

Histopathologic features

CD4 cell↑, granuloma edema, ↑ giant cell size and numbers, dermal edema and HLA-DR expression

Polymorphonuclear cell infiltrates in lesions 24 h old

Treatment

Corticosteroids

Corticosteroids, thalidomide

Recurrence

Approx. 30%

Approx. 65 %

BT, Borderline tuberculoid; BB, borderline borderline; BL, borderline lepromatous; ENL, erythema nodosum leprosum; HLA-DR, human leukocyte antigen-DR; LL, lepromatous lepromatous; TT, true tuberculoid.

Fig. 62.7  Female patient diagnosed with pauci-bacillary leprosy with single facial lesion showing type 1 reaction. The lesion has become acutely inflamed, swollen, and tender.

CHAPTER 62 Leprosy



Ethiopia.16 Azathioprine did not have a beneficial effect compared with prednisolone in a randomized controlled trial but may have a role as a steroid-sparing agent.17 There are case reports of methotrexate being used in T1R18 and NFI.19

Management of Erythema Nodosum Leprosum Reactions Type 2 leprosy reactions (i.e., ENL) present as a systemic illness: a patient with ENL may be very sick with high temperatures; painful subcutaneous nodules; peripheral edema; and inflammation of the nerves, eyes, joints, muscles, bones, and testes.20 The onset of ENL is acute, but it may pass into a chronic phase and is often recurrent (see Table 62.5). For mild ENL, aspirin may be used. Patients with severe ENL require hospitalization and treatment with high-dose prednisolone (starting at 60 mg). The efficacy is variable, and some patients with chronic, or recurrent, ENL may need to take prednisolone for several years.21 These long, high doses of steroids are associated with steroid side effects, such as hypertension, diabetes, cataracts, and acne.22 Thalidomide, starting at a dose of 100 to 400 mg daily and tapering down, is the treatment of choice for severe ENL.23 It controls ENL symptoms rapidly and prevents recurrences, but its availability and teratogenicity limit its use. Other alternatives to prednisolone, such as azathioprine, cyclosporine, pentoxifylline, and methotrexate, are being studied. Treatment with clofazimine improves ENL and is a mild anti-inflammatory. However, clofazimine therapy does not control severe ENL and takes 4 to 6 weeks to become active. The WHO recommends that clofazimine be used at 300 mg per day for 12 weeks then reduced to 200 mg for 12 weeks and maintained thereafter at 100 mg for 12 to 24 weeks.24

Management of Nerve Function Impairment NFI is defined as clinically detectable impairment of motor, sensory, or autonomic nerve function.25 NFI may occur in the absence of symptoms and may go unnoticed by the patient (i.e., “silent neuropathy”). NFI is detected clinically by testing the sensation in the patient’s hands and feet with graded monofilaments and testing the small muscles’ power. Patients seen with NFI of recent onset (less than 6 months) should be given a course of prednisolone therapy and physiotherapy. Some of these patients will recover function of the affected part.

Ongoing Management and Prevention of Complications Education concerning factual information, such as mode of transmission, infectivity, treatment, and complications, is essential for all patients and health care providers. Patients should be taught self-examination of the hands and feet with early medical review if signs of inflammation or trauma occur. Adequate footwear or other protective devices should be made available to those with insensitive or deformed feet. Ulcers in anesthetic feet are the most common cause of hospitalization. Ulcers are treated by rest and cleaning, although any signs of osteomyelitis need to be referred for surgical debridement. Appropriate early physiotherapy must be instituted, and patients must be referred to the appropriate specialist for evaluation and correction of deformity. Leprosy still elicits stigma in many communities, and the patient will benefit from social and psychological support.

Chemoprophylaxis and Immunotherapy To date, no specific vaccine has been developed to prevent infection by M. leprae, although there is good evidence that bacillus Calmette–Guérin (BCG) has protective efficacy. A meta-analysis

563

of 26 studies demonstrated an overall protective effect between 26% and 61%. The age at vaccination did not predict the protective effect of BCG.26 Protecting household contacts of leprosy patients has been explored by giving them a single dose of rifampin in Bangladesh. However, this intervention only protected against the development of pauci-bacillary leprosy and not multi-bacillary leprosy, and protection only lasted 2 years. This shows that preventing the development of leprosy is difficult.27

Leprosy and HIV There were concerns that an interaction between HIV and M. leprae infection would result in an increased incidence of leprosy cases. However, studies in Uganda, Mali, Ethiopia, and South India have not shown an increased prevalence of leprosy cases associated with HIV infection.28–30 An association has been found between HIV infection and complications of leprosy. In a casecontrolled study in Uganda, HIV seropositivity was found to be a significant risk factor for developing reactions and neuritis—an unusual finding because reversal reactions are associated with an increase in CD4 cells. Similarly, Sampaio et al found that HIVinfected patients with low CD4 counts had normal granuloma formation with numerous CD4 cells.31 A Brazilian study of 40 patients with leprosy and HIV co-infection demonstrated that there was no significant difference in the proportion of HIV-positive or -negative patients with T1R.32 Treatment of a leprosy patient with concurrent HIV infection does not differ from that of a seronegative leprosy patient, and reactions should be managed with corticosteroids or thalidomide as appropriate. Since the introduction of highly active antiretroviral therapy (HAART) in the management of HIV, leprosy is being increasingly reported as part of the immune reconstitution inflammatory syndrome (IRIS).32,33 It is possible that the immune response to M. leprae in an HIV-infected person is suppressed before starting HAART and that leprosy manifests as IRIS with the sudden reversal of this suppression and the rise of CD4.34 Further studies are needed to understand the clinical and pathologic features in HIV and leprosy co-infection.

CONCLUSION Since the implementation of MDT in 1982 in endemic areas, more than 90% of registered cases have received treatment, 15 million patients have been cured, and global prevalence has declined. The continuation of surveillance and leprosy control programs is essential. The current treatment for leprosy reactions is still not optimal, with a significant number of patients not responding to prednisolone, and some ENL patients requiring chronic thalidomide therapy. Researchers are still looking for different immunosuppressant drugs with efficacy in the treatment of reactions. The stigma associated with the diagnosis of leprosy is still a very real problem, and the management of someone with the disease should include discussion of their psychosocial status and education for the patient and their family. REFERENCES

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21. Pocaterra L, Jain S, Reddy R, et al. Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med Hyg 2006;74:868–79. 22. Richardus JH, Withington SG, Anderson AM, et al. Adverse events of standardized regimens of corticosteroids for prophylaxis and treatment of nerve function impairment in leprosy: results from the ‘TRIPOD’ trials. Lepr Rev 2003;74:319–27. 23. Nabarro LEB, Aggarwal D, Armstrong M, Lockwood DNJ. The use of steroids and thalidomide in the management of erythema nodosum leprosum; 17 years at the hospital for tropical diseases, London. Lepr Rev 2016;87:221–31. 24. WHO. WHO Expert Committee on Leprosy 8th Report; 2012. 25. Van Brakel WH, Khawas IB. Nerve damage in leprosy: an epidemiological and clinical study of 396 patients in west Nepal—part 1. Definitions, methods and frequencies. Lepr Rev 1994;65:204–21. 26. Setia MS, Steinmaus C, Ho CS, et al. The role of BCG in prevention of leprosy: a meta-analysis. Lancet Infect Dis 2006;6:162–70. 27. Moet FJ, Pahan D, Oskam L, Richardus JH. Effectiveness of single dose rifampicin in preventing leprosy in close contacts of patients with newly diagnosed leprosy: cluster randomised controlled trial. BMJ 2008;336:761–4. 28. Kawuma HJS, Bwire R, Adatu-Engwau F. Leprosy and infection with the human immunodeficency virus in Uganda.; a case-control study. Int J Lepr 1994;62:521–6. 29. Lienhardt C, Kamate B, Jamet P, et al. Effect of HIV infection on leprosy: a three year survey in Bamako, Mali. Int J Lepr Other Mycobact Dis 1996;64:383–91. 30. Sekar B, Jayasheela M, Chattopadhya D, et al. Prevalence of HIV infection and high-risk characteristics among leprosy patients of south India; a case-control study. Int J Lepr 1994;62:527–31. 31. Sampaio EP, Caneshi JRT, Nery JAC, et al. Cellular immune response to Mycobacterium leprae infection in human immunodeficiency virus infected individuals. Infect Immun 1995;63:18848–54. 32. Pires CA, Juca Neto FO, de Albuquerque NC, et al. Leprosy reactions in patients coinfected with HIV: clinical aspects and outcomes in two comparative cohorts in the Amazon region, Brazil. PLoS Negl Trop Dis. 2015;9(6):e0003818. 33. Deps PD, Lockwood DNJ. Leprosy occurring as immune reconstitution syndrome. Trans R Soc Trop Med Hyg 2008;102:966–8. 34. Ustianowski AP, Lawn SD, Lockwood DNJ. Interactions between HIV infection and leprosy: a paradox. Lancet Infect Dis 2006;6:350–60.