Review

Leprosy now: epidemiology, progress, challenges, and research gaps

Laura C Rodrigues, Diana N J Lockwood
Lancet Infect Dis 2011; 11: 46470 Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health (Prof L C Rodrigues PhD), and Department of Clinical Research, Faculty of Infectious and Tropical Diseases (Prof D N J Lockwood MD), London School of Hygiene and Tropical Medicine, London, UK Correspondence to: Prof Laura C Rodrigues, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK laura.rodrigues@lshtm.ac.uk

Leprosy continues to be a challenge to health worldwide, with about 250 000 new cases being detected every year. Despite widespread implementation of eective multidrug therapy, leprosy has not been eliminated. A third of newly diagnosed patients have nerve damage and might develop disabilities, although the proportion varies according to several factors, including level of self-care. Women who develop leprosy continue to be especially disadvantaged, with rates of late diagnosis and disability remaining high in this subgroup. Leprosy was not a specied disease in the Millennium Development Goals, but improvements in the other areas they cover, such as education and levels of poverty, will help leprosy patients and services. We review data and make recommendations for research on diagnosis, treatment, and prevention, such as further use of molecular analysis of the Mycobacterium leprae genome, implementation of BCG vaccination, and administration of chemoprophylaxis to household contacts. We also suggest development of tools for early diagnosis and detection of infection and nerve damage, and formulation of strategies to manage the chronic complications of leprosy, such as immune-mediated reactions and neuropathy.

Introduction
Leprosy is the leading infectious cause of disability.1 Prevalence has fallen substantially in the past 50 years,2 but transmission continues and leprosy remains a public health problem.3 Various hindrances remain to reducing this prevalence further. The mode of transmission of leprosy is not well understood, although it is probably person to person via nasal droplets.4 How many infected people develop clinical disease and whether reactivation of past infections is important are unknown. Although making a clinical diagnosis is frequently straightforward, no good point-of-care test is available for conrming it. Delay in diagnosis can have important negative outcomes, such as increased risk of nerve damage. Various factors contribute to delay, but stigma is an important feature in many cultures.5 Additionally, the immune responses and the mechanisms involved in nerve damage are not clearly understood; there is no predictive test for the extent of nerve damage and no good evidence on the best treatment. Type 1 and type 2 immune-mediated reactions continue to be major complications, and aect around 30% of patients. WHO has set a target for reducing the number of cases with grade 2 disability at diagnosis, but the feasibility of reporting disability accurately needs to be assessed. The integration of leprosy services into general health services has led to a loss of skills in the diagnosis and management of leprosy. WHO recommends multidrug therapy for 6 months in patients with paucibacillary disease (up to ve skin lesions) and for 12 months in patients with multibacillary disease (more than ve skin lesions).3 These regimens might, however, be insucient for patients with lepromatous disease and high bacterial indices, and no alternative drug regimens are currently recommended.6 Drug resistance has not so far been an issue with multidrug therapy,7 but monitoring is essential. Various areas of research are a priority in the worldwide management of leprosy. Contacts of leprosy patients are at increased risk of infection;8 chemoprophylaxis and BCG vaccination reduce this risk but the logistics, ethics,

and the cost-eectiveness of oering chemoprophylaxis are not simple. Research is needed, therefore, to inform future policies. New avenues for basic science and clinical research have been opened by sequencing the genome of Mycobacterium leprae and genome-wide analysis of leprosy cases.911 Genomic data might be useful in the development of drugs and vaccines against leprosy. Health-care features that require research are how to ensure equality in access to facilities for early diagnosis and to rehabilitation services, and ways to reduce stigma. In this Review we discuss the epidemiology of leprosy and the progress in and challenges to control, and make recommendations for research. The article is based on the review undertaken for the Disease-Specic Reference Group on tuberculosis, leprosy and buruli ulcer (one of the ten expert reference groups sponsored by the Special Programme for Research and Training in Tropical Diseases to assess the global research evidence on infectious diseases of poverty). We also take into account the WHO worldwide strategy for reducing the burden of disease related to leprosy,3 the decisions of its Technical Advisory Group on Leprosy Control,6 and the research ndings in leprosy from 200209 drawn together by the International Federation of Anti-Leprosy Organisations Technical Commission.5

History of leprosy and leprosy control

DNA analysis of M leprae strains suggests that this bacterium originated in Africa and spread to Asia and South America.9 Dapsone monotherapy was eective and was started in the 1940s. Lifelong administration was required, however, and in the 1960s widespread resistance was reported.12 In 1981, WHO recommended that all patients should receive multidrug therapy comprising rifampicin and dapsone, or rifampicin, dapsone, and clofazimine for patients with multibacillary disease. In 1995, a resolution was passed to provide free multidrug treatment to all leprosy patients worldwide.13
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The World Health Assembly passed a resolution in 1991 to eliminate leprosy as a public health problem by 2000; it dened elimination as reducing prevalence to less than one case per 10 000 population.14 The eort accompanying this resolution included the following features: the use of multidrug therapy and reclassication of all cases with removal after treatment completion, which is in contrast to cases being until death when treatment was lifelong. These actions on the registers, together with the widespread use of BCG vaccination, which was done to protect against tuberculosis but which also protects against leprosy, led to a marked reduction in prevalence.2 Nevertheless, leprosy was not eliminated and transmission continued, as use of the word elimination in the resolution had led to a perception that leprosy was about to disappear, and resulted in resources for leprosy research and control being reduced.3,8,12,15 When the WHO Strategic Plan for Leprosy Elimination was renewed, the word elimination was replaced by the phrase reducing leprosy burden; this term encompasses the direct burden of disease and the related burden of disability.1 The Millennium Development Goals were agreed at the Millennium Assembly of the UN in 2000, and committed the states of the world to a global development project that was summarised in eight goals: eradicate extreme poverty and hunger; achieve universal primary education; promote equality for both sexes and empower women; reduce child mortality; improve maternal health; combat HIV/AIDS, malaria, and other diseases; ensure environmental sustainability; and build a global partnership for development.16 Leprosy is not explicitly listed in any of the goals, but those relating to poverty, primary education, and building a global partnership are relevant to leprosy control. Disability is also not explicitly included in the goals, but various ways of integrating it have been suggested.1 In 2008, the UN Enable Convention on the Rights of Persons with Disabilities17 was enacted, and the UN Human Rights Council passed a resolution on the elimination of discrimination against people aected by leprosy and their family members.18 There has been concern that Millennium Development Goals might have caused an imbalance in the development agenda, and especially that the focus on HIV/AIDS and malaria might perpetuate the neglect of other diseases, including leprosy.19 Leprosy is a disease of poverty. The ensuring of equal access to diagnostic and rehabilitation facilities and to treatment, as well as the prevention of disability, is, therefore, important.

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Figure: Incidence (new-case detection rate) and prevalence of leprosy in (A) India22 and (B) Brazil23

Epidemiology
The new case detection rate for leprosy remains high, with about 250 000 new cases being registered each year. Around 15 million people have been treated with multidrug therapy, and an estimated 2 million people have been prevented from developing disabilities.12 Although the leprosy prevalence values fell strikingly
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from 620 638 cases in 2002, to 213 036 in 2009,20,21 this decrease is due partly to the prevalence vlaues being halved by the duration of treatment being reduced from 24 months to 12 months. Prevalence is also aected by operational factors, such as level of case nding activity and integration of leprosy services into primary-healthcare services in some countries so that the leprosy elimination targets would be reached. Data for prevalence and incidence for India and Brazil are shown in the gure. These data clarify the importance of using the new case detection rate as a marker of transmission of leprosy. High numbers of new cases continue to be detected249 000 were reported in 2008, of which 94% were in the 17 countries that had reported detecting more than 1000 new cases in that year.20,24 As shown in the gure, the new case detection rates in Brazil continue to be high. These data indicate ongoing transmission of leprosy. A survey done in Maharashtra, India, showed rates of three to nine cases per 10 000 population, and that 30% of these newly diagnosed cases were in children.
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A consensus has been reached by WHO that close disease surveillance for leprosy is necessary, and four indicators have been suggested: the number of new cases, the new case detection rate, the treatment completion rate (or, when feasible, cure rate), and the rate of new cases with grade 2 disabilities.3 A new target was introduced that the number of new cases with grade 2 disability in 2015 should be 35% lower than in 2010. Monitoring of the rate of new cases with disability will pose challenges, in view of the uncertainties about the reliability of the data. Thus, tools for accurate, comparable grading practices are needed. Various instruments for measuring disabilities are available,25 but their applicability to leprosy needs to be tested. The 2009 WHO Technical Advisory Group report recommended convening a working group to review current practice for data collection, reporting, and analysis to ensure that the target is valid.6

Transmission
Leprosy is caused by M leprae. Most people infected with this organism are thought not to develop clinical disease, although there are no tools to diagnose subclinical infection. M leprae is slow growing and the incubation period of leprosy is long at 212 years. The mode of transmission is still not conclusively proven, although person-to-person spread via nasal droplets is believed to be the main route.4 Human beings are the principal reservoir of infection, except in the Americas, where armadillos also provide a reservoir;26 the proportion of cases attributable to armadillos is unknown, but progress is being made in the estimation and two-thirds of acquired cases in southern USA have armadillo-derived strains of M leprae in the lesions.27 Most people with leprosy are non-infectious as the mycobacterium remains intracellular. Patients with lepromatous leprosy, however, excrete M leprae from their nasal mucosa and skin28 and are infectious before starting treatment with multidrug therapy. Contacts of these patients are, therefore, at increased risk of developing leprosy.7 The magnitude of this risk depends on the closeness of contact,7 with close household contacts being at the highest risk. The risk of disease in contacts is also related to the bacterial load of the primary case, with the risk being twice as high in contacts of multibacillary cases as in those of paucibacillary cases. Whether genetic predisposition has a role in the development of leprosy is unclear.7 Gene candidates for susceptibility to leprosy infection have been reported, but replication of these ndings has been dicult. A genomewide association study of leprosy patients and healthy controls identied new associations between variants of genes in the NOD2-mediated signalling pathway, which regulates the innate immune response, and determines the risk and form of disease.7 The genome sequence of M leprae has been available since 2001.29 Work on strain typing of M leprae has used
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either single-nucleotide polymorphisms or short or variable number tandem repeat genotyping. Early work with single-nucleotide polymorphisms revealed four subtypes of M leprae and postulated a route of spread around the world.9 This work has been extended after four whole-genome sequences from Brazil, India, Thailand, and the USA were analysed, in which 201 single-nucleotide polymorphisms and 14 singlebase insertions or deletions were identied.9 This analysis identied 16 single-nucleotide polymorphism subtypes across 400 isolates.9 The low degree of polymorphism arising from the four strains, for which the genomes are 99995% identical, suggests that there is little variation in M leprae. Short or variable number tandem repeat genotyping has classied M leprae strains in several countries.11 A potential limitation of this method is that many loci have to be analysed to classify strains. One analysis used genotypes from 475 M leprae strains and six dierent countries, and the ndings suggested that most M leprae strains cluster together within specic countries, and that the presence of isolates assigned to dierent clusters is a consequence of migration.11 Some ndings were, however, surprising, including that the Indian strain seems to have derived from a Philippine strain. The short or variable number tandem repeat and singlenucleotide polymorphism genotyping methods are best seen as being complementary. Single-nucleotide polymorphism analysis can be slow and the tandem repeat method identies many dierences and is dicult to use for epidemiological analysis apart from showing the existence of short transmission chains in families. Relapse is rare in leprosy, occurring in less than 1% of patients and frequently 10 or more years after treatment. These molecular tools are not, therefore, practical to assess whether infection reactivation or new infection is occurring. They could, however, be used to investigate whether clinical outcomes, such as erythema nodosum leprosum, are associated with dierent strains and whether the M leprae strain infecting armadillos is the same as any infecting human beings.26,27 Molecular techniques might also clarify the mechanisms behind the survival, persistence, and pathogenicity of M leprae.9,3032

Clinical disease
Infection with M leprae leads to chronic granulomatous inammation in skin and peripheral nerves. The type of leprosy that patients develop is determined by their cellmediated immune response to infection. Types may be categorised according to the Ridley-Jopling classication,33 which is based on skin lesion type and bacterial load. Patients with tuberculoid disease have good cell-mediated immune response and few lesions with no detectable mycobacteria. Patients with lepromatous leprosy are anergic towards M leprae and have multiple lesions with mycobacteria present. Between these two classications are the borderline leprosy types, in which patients have
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some cell-mediated immune response, multiple lesions, and unstable immunity. WHO has introduced a simplied classication that uses the number of skin lesions to classify disease as paucibacillary (up to ve lesions) or multibacillary (more than ve skin lesions). This classication is widely used to guide treatment decisions. Comparison of the two classication systems showed that in India up to 60% of the patients with borderline tuberculoid (in the Ridley-Jopling classication) assigned to the WHO multibacillary group had negative slit skin smear. These patients were, therefore, being overtreated.34 The importance of using the more rigorous classication in referral centres and for research studies has been highlighted.35 Damage to nerves can occur before, during, and after treatment and can result in disability and long-term disgurement, which is associated with stigma.36 A cohort study in Ethiopia showed that 47% of 594 new cases already had established nerve function impairment at diagnosis and that a further 8% had recent nerve damage. Additionally, 12% developed nerve damage after the start of treatment, and only 33% had no clinical evidence of nerve involvement at any time.37 The degree of nerve damage at diagnosis reects the delay between the onset of symptoms and diagnosis. The delay is frequently years, and during this time neuropathy can develop almost unnoticed. Many nerves at diagnosis are non-conducting and remain so.34,38,39 The inammation present in nerves is driven by mycobacterial antigens that activate a destructive inammatory immune response mediated by CD4+ cells and macrophages, and with involvement of multiple proinammatory cytokines, such as tumour necrosis factor . Markers of progression to neurological damage have not been identied.40 A better understanding of the immune responses behind the nerve damage would identify high-risk patients for closer monitoring and early intervention with existing therapies, and guide the development of preventive and modulating interventions.38 Type 1 and type 2 immune-mediated reactions occur in about 30% of patients with multibacillary disease during and after multidrug therapy.41 Steroids are the main treatment, but a systematic review found only three trials of adequate quality that supported this strategy.42 An evidence-based review done by the International Federation of Anti-Leprosy Organisations found that the optimum duration of steroid treatment is unknown, although some data suggest that longer courses are better, as 20 weeks of treatment yielded better results than 12 weeks of treatment in one study.43 No studies have used a dose-per-weight regimen. The relapse rate after steroid therapy is 2050%.44 Standardised tools are needed to measure outcomes and enable comparison of study ndings. Second-line drugs for the treatment of patients who do not respond to prednisolone are also needed.45
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Erythema nodosum leprosum reactions occur in about 50% of patients with lepromatous leprosy.46 These episodes of systemic inammation aect skin, nerves, eyes, and testes and are dicult to manage.47 Reactions may remit and relapse over several years. Few studies have been done to investigate the pathogenesis and treatment of erythema nodosum leprosum. One review identied only three studies published in the past 20 years.47 Current treatments include steroids and thalidomide, but studies done with internationally validated severity scales are needed to identify the best treatment regimens.48 In many countries thalidomide is not available because of fears relating to its teratogenic potential. An international research network to facilitate studies on pathogenesis and improved treatments in linked centres would be benecial. Identication of eective treatment for post-partum women is especially important, as they are at particularly high risk of reactions, but are frequently under-represented in trials.48 Owing to the similarities between tuberculosis and leprosy, early in the HIV-1 epidemic it was feared that HIV-1 infection would increase the risk of developing leprosy, especially lepromatous leprosy, or that dually infected people would have leprosy that was particularly severe or with a poor prognosis. Although data on patients infected with HIV and leprosy are sparse, none of these fears has been conrmed.49 Two Brazilian studies have shown that patients receiving highly active antiretroviral therapy are more likely to develop borderline tuberculoid leprosy than other types of leprosy.50,51 In HIV-1-infected patients starting antiretroviral treatment, leprosy has presented as immune reconstitution inammatory syndrome.52,53 In a review of published cases of leprosy manifesting as this syndrome, presentations were classied according to timing as either unmasking or as a paradoxical clinical worsening of pre-existing leprosy: 12 (58%) were unmasking, two (9%) were paradoxical, two (9%) were undiagnosed, and ve (24%) were unmasking followed by immune restoration.54

Treatment
WHO recommends multidrug therapy with rifampicin and dapsone for paucibacillary disease, or with rifampicin, dapsone, and clofazimine for patients with multibacillary disease. The recommended duration of therapy is 6 months for patients with paucibacillary disease and 12 months for those with multibacillary disease, and these regimens will eectively eradicate M leprae in most patients. The 2009 report of the WHO Technical Advisory Group on Leprosy Control stated clearly that in public health terms, it is reasonable to conclude that infectiousness becomes unlikely after starting multidrug therapy.6 Longer treatment might, however, be required in some patients with a high bacterial index at diagnosis to prevent relapse.6 At least one current trial is comparing dierent durations of treatment for multibacillary leprosy.6
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People with lepromatous multibacillary disease are the main source of M leprae, and if relapse occurs in these patients transmission resumes. This form of the disease is, therefore, particularly important from a public health perspective. The rate of relapse after multidrug therapy varies, mainly owing to dierent follow-up methods and denitions, but is at least below three cases per 100 personyears, and seems to be mostly lower than two cases per 100 person-years. Factors associated with relapse include use of monotherapy, inadequate or irregular therapy, lack of response, presence of multiple skin lesions or thickened nerves, and no reaction to the lepromin skin test.55 Accurate diagnosis of relapse requires clinical, bacteriological, and therapeutic evidence; histopathology can be helpful but frequently is not routinely available.55 The current WHO recommendation is that multidrug therapy is restarted in cases of proven relapse.3 Relapse and type 1 immune reaction can both lead to new skin lesions and loss of nerve function. Drug resistance is not yet a major issue. Patients suspected of having resistant strains of M leprae have responded to re-treatment with rifampicin, dapsone, and clofazimine.3 Testing for resistance involves inoculating mouse footpads with a patients tissue obtained at biopsy and observing M leprae growth. This method is now complemented by DNA sequencing to identify gene mutations associated with drug resistance. Genes coding for resistance to rifampicin, ooxacin, and dapsone have been identied.6 However, the clinical importance of bacteria having a particular resistance gene remains unknown. A worldwide surveillance initiative to assess drug resistance in leprosy has been set up.6 The WHO Technical Advisory Group has encouraged expanding the work in selected countries.6 This and similar research needs to be well supported, as no new antibiotic drugs are in development for treating leprosy but alternative treatment regimens are needed. Increased capacity for drug screening, experimental chemotherapy, and clinical trials is also required to regain treatment knowledge lost with the success of multidrug therapy.

challenge. Richardus and Habbema59 have argued that to eradicate an infectious disease one needs an intervention that can interrupt transmission, practical diagnostic tools with sucient sensitivity and specicity to detect all levels of infection that can lead to transmission, and the absence of a reservoir. On the basis of these principles, they suggest that extensive epidemiological and microbiological research be done to identify good tools to detect infection, and that new interventions, such as chemoprophylaxis and vaccination, should be developed and implemented.59 Serological tests for detection of infection and to monitor progress under treatment have been of interest for some time. Such tests might also be useful to identify contacts, to monitor transmission in the community, and to guide treatment. A range of tests are available, although none is suciently specic and sensitive for leprosy. Sekar60 noted that improvements have been made in several immunological diagnostic tests. Developments include assays for antibodies to PGL-1 (eg, dipstick, ELISA, ML Flow test); new skin test antigens, such as M leprae soluble antigens and lipoarabinomannan, wall-associated proteins of M leprae, and their fractionates; translation of tools from research on immunological diagnosis of tuberculosis, such as CFP-10 and ESAT-6 proteins; and novel M leprae-specic antigens identied after the genome sequencing of the organism, including overlapping short peptides of dierent recombinant proteins to identify specic B-cell and T-cell epitopes.60 A more detailed review of these methods is outside the scope of this paper.

Prevention
Chemoprophylaxis eectively lowers the incidence of leprosy in household contacts.61 Whether to use this approach more widely is under discussion. Single-dose rifampicin can prevent progression of disease in people infected with leprosy but only in non-close contacts with low bacterial loads.61 Fears of resistance with use of monotherapy, however, have led to the suggestion that one or two doses of 600 mg rifampicin, 400 mg ooxacin, and 100 mg minocycline should be used.5 This regimen would, however, be far more expensive. The extension of chemoprophylaxis to close nonhousehold contacts is supported by a good epidemiological argument, but various practical issues could hinder implementation of this policy. For example, disclosure of leprosy in the index case required for identication of contacts, especially outside the home, might be undesirable or unethical.61 The current recommendation in WHOs Enhanced Global Strategy for Further Reducing the Disease Burden due to Leprosy10 is to examine household contacts of patients for evidence of leprosy, if none is found to educate the contacts on early signs of disease, and to return if these develop. The latest report from WHOs Technical Advisory Group on Leprosy Control6 recommends that a working group be formed to review the present data
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Diagnosis
Late diagnosis leads to continued transmission and to increased risk of disability.15 Factors associated with late diagnosis include delay by patients in presenting and delay by health services in making a diagnosis. Reasons behind patients delaying presentation vary from setting to setting,56 but stigma is likely to play a part in many cases.5 In some countries stigma is promoted by legislation against leprosy patients.5 Other inequalities also aect people with this disease. Reports from Ethiopia and Bangladesh57,58 have shown that women experience longer delays than men in diagnosis and, therefore, frequently have a higher degree of nerve damage and disability at diagnosis. With decentralisation of treatment and monitoring and decreasing numbers of cases, the maintenance of expertise in leprosy at the peripheral level is a major
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on chemoprophylaxis and to advise on areas of research with the aim of developing appropriate guidelines for implementation in future leprosy control strategies. Vaccination with BCG protects people from developing leprosy, and neonatal BCG vaccination given to prevent tuberculosis has probably contributed substantially to the decrease in prevalence of leprosy. BCG is a live vaccine and, therefore, use should be avoided in people infected with HIV. As with tuberculosis, the degree of protection against developing leprosy obtained from BCG varies between populations, but the reasons for this variation are not clearly understood.2 BCG vaccination of contacts seems to be protective even in contacts who have already received neonatal BCG.62,63 The timing of vaccination and chemoprophylaxis should be considered because chemoprophylaxis can kill BCG. The search for a modern, subunit protein vaccine has been facilitated by the sequencing of M leprae, although it is much less advanced than for tuberculosis vaccines. The main reason for the slow progress is cost-eciency, as leprosy is much rarer than tuberculosis and the incidence has been declining. Additionally, in contrast to tuberculosis, there is no suitable animal model; pathogenesis in mice is atypical and armadillos are not practical for vaccine testing.64,65 If a more specic tuberculosis vaccine is proposed to replace rather than to boost BCG, the protection against leprosy given by current BCG vaccination will be lost. Development of an improved leprosy vaccine or exploration of the possibility of adding protection against leprosy to any new tuberculosis vaccine, therefore, also need to be urgently explored. Findings during the development of antituberculosis vaccines might shed some light on the mechanism behind immunity to mycobacteria and help the search for a new leprosy vaccine.64

Search strategy and selection criteria We reviewed the recommendations for research from the Leprosy International committees, and selected a list of relevant topics. We used the term leprosy with each of drug resistance, nerve damage, detection and diagnosis of early infection, nerve damage, vaccines, chemoprophylaxis, diagnosis/grading disability, new treatment regimens for leprosy and for reactions, the role of armadillo, transmission, reactivation, patient and health services delays in diagnosis, stigma, and research priorities to search for papers published from 2006 in PubMed, Medline, Web of Science, and Cielo. We reviewed abstracts and full-text articles published in English, French, Italian, and Portuguese languages, and followed up relevant citations in the reference lists of retrieved papers.
Contributors Both authors worked equally on developing the structure for the paper, identifying references, writing, and editing the paper. Conicts of interest We declare that we have no conicts of interest. Acknowledgments We thank the Special Programme for Research and Training in Tropical Diseases, and the Disease-Specic Reference Group on Tuberculosis, Leprosy and Buruli Ulcer for support and advice during the preparation of this Review. References 1 United Nations Enable. The Millennium Development Goals (MDGs) and Disability. 2009. http://www.un.org/disabilities/ default.asp?id=1470 (accessed Jan 25, 2010). 2 Merle CS, Cunha SS, Rodrigues LC. BCG vaccination and leprosy protection: review of current evidence and status of BCG in leprosy control. Expert Rev Vaccines 2010; 9: 20922. 3 WHO. Enhanced global strategy for further reducing the disease burden due to leprosy (plan period: 20112015). New Delhi: World Health Organization Regional Oce for South-East Asia, 2008. 4 Hatta M, van Beers SM, Madjid B, Djumadi A, de Wit MY, Klatser PR. Distribution and persistence of Mycobacterium leprae nasal carriage among a population in which leprosy is endemic in Indonesia. Trans R Soc Trop Med Hyg 1995; 89: 38185. 5 Senior K. Stigma, chemoprophylaxis, and leprosy control. Lancet Infect Dis 2009; 9: 10. 6 WHO Technical Advisory Group on Leprosy Control. Report of the Tenth Meeting of the WHO Technical Advisory Group on Leprosy Control. New Delhi: World Health Organization Regional Oce for South-East Asia, 2009. 7 Arungiri S, et al. Detection of mutations in folp1, rpoB and gyrA genes of M. leprae by PCR- direct sequencinga rapid tool for screening drug resistance in leprosy. Lepr Rev (in press). 8 Moet FJ, Meima A, Oskam L, Richardus JH. Risk factors for the development of clinical leprosy among contacts, and their relevance for targeted interventions. Lepr Rev 2004; 75: 31026. 9 Monot M, Honore N, Garnier T, et al. Comparative genomic and phylogeographic analysis of Mycobacterium leprae. Nat Genet 2009; 41: 128289. 10 Zhang FR, Huang W, Chen SM, et al. Genomewide association study of leprosy. N Engl J Med 2009; 361: 260918. 11 Gillis T, Vissa V, Matsuoka M, et al. Characterisation of short tandem repeats for genotyping Mycobacterium leprae. Lepr Rev 2009; 80: 25060. 12 Scollard DM, Adams LB, Gillis TP, Krahenbuhl JL, Truman RW, Williams DL. The continuing challenges of leprosy. Clin Microbiol Rev 2006; 19: 33881. 13 Feasey N, Wansbrough-Jones M, Mabey DC, Solomon AW. Neglected tropical diseases. Br Med Bull 2010; 93: 179200. 14 World Health Assembly. World Health Assembly resolution 1991. http://www.who.int/lep/strategy/wha/en/index.html (accessed Jan 25, 2010). 15 Burki T. Old problems still mar ght against ancient disease. Lancet 2009; 373: 28788. 16 UN. We can end poverty 2015: Millennium Development Goals. http://www.un.org/millenniumgoals (accessed Jan 25, 2010).

Conclusions
Priorities for research in leprosy cover a wide range of areas, from basic science to health services. Further understanding is needed of the epidemiology, including transmission, the role of the armadillo, and relative contributions of transmission and reinfection to the overall disease burden, and of the pathogenesis of nerve damage. Eective tools must be developed for detection of early infection, for point-of-contact diagnosis, to predict nerve damage, and to grade disability. New treatment regimens for leprosy and for immune-mediated reactions need to be developed and thoroughly tested. Finally, eective methods for monitoring drug resistance have to be implemented. For prevention and health services research, development of a new vaccine or incorporation of a leprosy component into new antituberculosis vaccines is crucial. Delivery strategies for chemoprophylaxis of contacts need to be assessed, and delays to diagnosis, discrimination, and stigma must be substantially reduced. We hope that researchers and funding will be available to take up these challenges.
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