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EDITORIAL
Year : 2019  |  Volume : 149  |  Issue : 1  |  Page : 1-4

Unfinished business - Leprosy still not defeated


Former Director, National Hansen's Disease Program, 1770 Physicians Park Dr, Baton Rouge, LA 70816, USA

Date of Submission04-Jan-2019
Date of Web Publication22-Apr-2019

Correspondence Address:
David M Scollard
Former Director, National Hansen's Disease Program, 1770 Physicians Park Dr, Baton Rouge, LA 70816
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmr.IJMR_12_19

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How to cite this article:
Scollard DM. Unfinished business - Leprosy still not defeated. Indian J Med Res 2019;149:1-4

How to cite this URL:
Scollard DM. Unfinished business - Leprosy still not defeated. Indian J Med Res [serial online] 2019 [cited 2019 Oct 17];149:1-4. Available from: http://www.ijmr.org.in/text.asp?2019/149/1/1/256696

This editorial is published on the occasion of World Leprosy Day - January 30, 2019


Nearly everything about leprosy happens slowly. The germ divides once every two weeks, the incubation time is several years and the dead bacilli often linger in tissues for years even after being killed with antimicrobial drugs. So perhaps it is no surprise that it has taken nearly two decades to steer a course correction in the global approach to leprosy diagnosis and treatment. Medical and public health aspirations for the elimination of leprosy got ahead of the scientific knowledge about how to accomplish this, promising elimination by specific dates, and even a vote in the World Health Assembly declaring that it had been done (www.who.int/lep/strategy/who/en/). But here we are, nearly 20 years later, still working on it.

The new course in pursuit of victory against leprosy has been charted upon two major developments. First - the WHO's application of evidence-based methodology to develop their plan. Second - a three-part strategy to seek zero transmission, zero disability and zero stigma. The International Federation of Anti-leprosy Associations (ILEP), the WHO and the newly organized Global Partnership for Zero Leprosy (GPZL) are all aligned with this approach.

The new WHO guidelines pointedly note that the new recommendations are evidence based[1]. Very few other diseases have lagged so far behind that the medical and public health policies guiding them into the 21st century were based primarily on expert opinion. The fact that the WHO has adopted a process to review and assess available scientific evidence in deciding on policy is a truly positive development. While there is still controversy about the quality and quantity of the evidence[2], the fact that the discussion now is about the evidence, rather than arguments over opinions, is an important step forward.

In the past, the paucity of evidence was only part of the problem; good evidence (though less sophisticated) was available. The other part of the problem has been, to put it simply, human nature. In the earnest desire to eliminate Hansen's disease, ambitious planning did not always heed the limitations identified by existing scientific evidence. The plan to eliminate leprosy as a public health problem oversimplified this complex disease[3], and the programme itself was overly simplistic in its expectation of what could be achieved by treatment alone. A much wider range of voices now appears to be involved in making decisions about objectives and policies. Hopefully, this will result in plans consistent with the best scientific and medical evidence.

The three-part strategy of ILEP, WHO and GPZL is, at least in part, a recognition of the oversimplification of the past policies. The new approach is a more nuanced one, recognizing that victory in resolving the different aspects of this disease requires different tools and methods, and allows that each will have its own metrics and proceed at its own pace, determined by relevant scientific and medical advances.

Zero transmission is a lofty goal when we realize that the mechanisms of transmission of Mycobacterium leprae are so poorly understood. However, several technical developments bring new tools to address this, including molecular methods to assess the killing of M. leprae, genotyping, vaccines and possible prophylactic measures. Transmission has not been interrupted in all areas by treatment with multidrug therapy (MDT) alone, in spite of the benefits to millions of people that have been achieved through the WHO's MDT programme. This is well illustrated by the results of the recent national survey in India[4]. The number of new cases was low in many areas but remained high in several others. To improve results with MDT, leprosy programmes need an improved and shortened treatment regimen. Among the obstacles in achieving this, the inability to culture the pathogen has required slow, expensive and technically demanding mouse-footpad assays to assess the efficacy of individual drugs. Even slower, expensive and years-long clinical trials have been required to assess relapse as an outcome, to determine if a regimen is efficacious in the field. A molecular viability assay[5] can now determine the efficacy of individual drugs or new regimens by assessing the killing of M. leprae directly from skin biopsies. Field trials of this method are in progress (Linda Adams, personal communication). This technique may offer new opportunities to obtain strong evidence in a short time, enabling scientists and clinicians to craft a highly efficacious, short regimen.

Addressing transmission on a public health scale, molecular advances in M. leprae genotyping[6] are likely to make molecular epidemiology an important tool to follow the path of M. leprae infection in defined regions. Genotyping of M. leprae is still technically demanding when compared to the rapid strain-typing that is possible for most other bacterial infections, but when combined with geographical positioning system (GPS)-assisted fine mapping of cases, it promises to provide public health programmes with highly valuable information.

A vaccine for leprosy has been a goal of immunological research on leprosy for several decades. Recently, a defined subunit vaccine has been developed[7] composed of defined M. leprae antigens and administered together with a new toll-like receptor-4 activating adjuvant. When tested on experimentally infected armadillos, this vaccine has yielded surprising results: it delayed the onset and reduced the severity of nerve conduction deficits due to leprosy. If these findings are confirmed in human patients, this candidate vaccine could provide a revolutionary new tool to interrupt the development of nerve injury in this disease, in addition to whatever benefit it may have in preventing transmission.

Another possible means of interrupting transmission is prophylactic treatment of contacts, to prevent recently acquired M. leprae from developing into an infection. While simple in concept and therefore attractive, prophylaxis against leprosy has been difficult to achieve in practice. Renewed interest in post-exposure prophylaxis (PEP) has been generated by findings from trials of a single dose of rifampin (SDR) given to contacts or to entire communities[8],[9]. For PEP to be implemented effectively, a good public health programme of contact tracing must be in place, or be developed first. This itself is a challenge and requires commitment of resources; but when accomplished, such a programme is a major benefit to any control regimen anywhere. Evidence thus far also indicates that SDR has important limitations, as the closest contacts receive the least benefit[10]. The concept of prophylaxis remains attractive, nevertheless, and PEP projects are being implemented in several countries[11].

The development and implementation of vaccines and PEP initiatives, and assessment of their effectiveness in interrupting transmission, require improved techniques for early diagnosis to assess the extent of transmission. Substantial research activity continues in this area, attempting to develop tests based on circulating antibodies as well as markers of cellular immunity[12]. As with past efforts, antibody-based tests fail to identify a large percentage of paucibacillary patients[12]. Assessing cellular immune capability through circulating markers as a means of early detection of these cases is a newer effort in leprosy, and the capability to do this in the field remains to be determined.

Zero disability as a goal confronts the unique fact that M. leprae infects nerves. Disabilities are the sequelae of leprosy, and these may persist even when the infection has been effectively treated and bacilli have been killed. The main focus of disability prevention in leprosy is based on treatment of the infection. On the premise that less disability implies more recent infection, earlier diagnosis and treatment are the next logical steps. This argument proposes that disability prevention by MDT can therefore, be measured by following the percentage of newly diagnosed cases that have Grade 1 or Grade 2 disability. However, the extent of disability at the time of diagnosis does not assess the full extent of disability in leprosy because patients may continue to develop nerve injury (with or without reactions) during MDT and even after completion of MDT. Emphasis on early diagnosis is valuable, but it is not sufficient to achieve zero disability in leprosy. The underlying cause of most disability in leprosy is nerve injury, and in understanding this, we still face many challenges. There are probably several mechanisms of nerve injury operating in many patients simultaneously, and we still have a very poor understanding of any of them. The availability of an animal model offers opportunities for investigation that have previously been impossible, but the fact that the animal is the armadillo also makes the task very challenging[13]. To prevent or reduce disability in leprosy, there must be an increased emphasis on research to understand the mechanisms of nerve injury in leprosy, in addition to continuing efforts at early diagnosis.

Zero stigma in leprosy is probably the most challenging goal of all. The increasing emphasis on understanding and fighting against discrimination, stigma and prejudice - the theme of World Leprosy Day this year - is perhaps the sharpest reminder of how far we must go beyond just curing infection with M. leprae[14]. Notably, disability is a major factor in generating and perpetuating stigma and discrimination, and advances in the scientific understanding of nerve injury can make a major contribution to the reduction in stigma and discrimination as well. However, social and cultural factors are also major determinants of stigma, and these are not amenable to technical solutions. That is, early diagnosis, shorter treatment regimens, vaccines, prophylaxis and even better treatment of nerve injury will not in themselves eliminate stigma. For this reason, localized research efforts are necessary to understand the particular social and cultural factors operating in each country or region and to determine how to successfully address them. Research of this type has probably been underemphasized in the past. The Leprosy Research Initiative, a major source of support for field research in leprosy, has funded several such projects and continues to emphasize this as one of its priorities[15]. Issues of stigma are also encountered in many of the other 'Neglected Tropical Diseases', and studies of stigma in leprosy can both benefit from and contribute to this wider area of research[16].

The advances mentioned above are only some of the many efforts that offer significant promise for improvements in management and control of all aspects of leprosy. Maintaining surveillance is critical and very challenging in the face of other pressing medical problems worldwide. When the disease in a particular region has been reduced to a small number of patients - or even 'zero' - the job is not finished. Ministries of health must be strongly advised to maintain careful surveillance for leprosy. Based on the known incubation period, it would be wise to maintain careful surveillance for at least 10 years. Moreover, as dedicated leprosy programmes have been reduced or eliminated, more and more patients are being treated by physicians with little or no knowledge of or experience with leprosy. Leprosy must remain in the medical curriculum.

Global cooperative efforts to coordinate work towards zero transmission, zero disability and zero stigma will require concerted effort. Developing policy based on evidence requires better evidence. The research underway is valuable, but findings must be viewed critically and cautiously. For example, the enthusiasm for PEP is eerily reminiscent of the enthusiasm and expectation in the recent past that MDT alone could eliminate leprosy. Similarly, the aspiration for vaccines and early diagnostic tests may exceed the technical capability of the methods available. Patience is required until enough new findings provide clear evidence of benefit in the field. For victory over leprosy and its many consequences, much unfinished business remains.

Conflicts of Interest: None.



 
   References Top

1.
World Health Organization. Guidelines for the diagnosis, treatment and prevention of leprosy. New Delhi: WHO, Regional Office for South East Asia; 2018.  Back to cited text no. 1
    
2.
Lockwood DNJ, Walker SL, Lambert S, Srikantam A, Darlong J, Pai VV, et al. Little evidence to support a major change in paucibacillary leprosy treatment in the 2018 WHO treatment guidelines. Leprosy Mailing List Dec. 23, 2018. Available from: https://groups.google.com/forum/#!topic/leprosymailinglist/qJt3KoMp5U4. accessed on December 25, 2018.  Back to cited text no. 2
    
3.
Lockwood DN, Suneetha S. Leprosy: Too complex a disease for a simple elimination paradigm. Bull World Health Organ 2005; 83 : 230-5.  Back to cited text no. 3
    
4.
Katoch K, Aggarwal A, Yadav VS, Pandey A. National sample survey to assess the new case disease burden of leprosy in India. Indian J Med Res 2017; 146 : 585-605.  Back to cited text no. 4
    
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Davis GL, Ray NA, Lahiri R, Gillis TP, Krahenbuhl JL, Williams DL, et al. Molecular assays for determining Mycobacterium leprae viability in tissues of experimentally infected mice. PLoS Negl Trop Dis 2013; 7 : e2404.  Back to cited text no. 5
    
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Truman RW, Singh P, Sharma R, Busso P, Rougemont J, Paniz-Mondolfi A, et al. Probable zoonotic leprosy in the Southern United States. N Engl J Med 2011; 364 : 1626-33.  Back to cited text no. 6
    
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Duthie MS, Pena MT, Ebenezer GJ, Gillis TP, Sharma R, Cunningham K, et al. LepVax, a defined subunit vaccine that provides effective pre-exposure and post-exposure prophylaxis of M. leprae infection. NPJ Vaccines 2018; 3 : 12.   Back to cited text no. 7
    
8.
Cartel JL, Chanteau S, Moulia-Pelat JP, Plichart R, Glaziou P, Boutin JP, et al. Chemoprophylaxis of leprosy with a single dose of 25 mg per kg rifampin in the Southern Marquesas;results after four years. Int J Lepr Other Mycobact Dis 1992; 60 : 416-20.  Back to cited text no. 8
    
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Moet FJ, Pahan D, Oskam L, Richardus JH; COLEP Study Group. 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.  Back to cited text no. 9
    
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Lockwood DNJ, Krishnamurthy P, Kumar B, Penna G. Single-dose rifampicin chemoprophylaxis protects those who need it least and is not a cost-effective intervention. PLoS Negl Trop Dis 2018; 12 : e0006403.  Back to cited text no. 10
    
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Gillini L, Cooreman E, Wood T, Pemmaraju VR, Saunderson P. Global practices in regard to implementation of preventive measures for leprosy. PLoS Negl Trop Dis 2017; 11 : e0005399.  Back to cited text no. 11
    
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van Hooij A, Geluk A. Immunodiagnostics for leprosy. In: Scollard DM, Gillis TP, editors. International textbook of leprosy. 2016. Available from: http://www.internationaltextbookofleprosy.org/chapter/immunodiagnostics-leprosy, accessed on December 22, 2018.  Back to cited text no. 12
    
13.
Sharma R, Lahiri R, Scollard DM, Pena M, Williams DL, Adams LB, et al. The armadillo: A model for the neuropathy of leprosy and potentially other neurodegenerative diseases. Dis Model Mech 2013; 6 : 19-24.  Back to cited text no. 13
    
14.
Rao PS, Raju MS, Barkataki A, Nanda NK, Kumar S. Extent and correlates of leprosy stigma in rural India. Indian J Lepr 2008; 80 : 167-74.  Back to cited text no. 14
    
15.
Leprosy Research Initiative. Available from: https://www.leprosyresearch.org, accessed on December 25, 2018.  Back to cited text no. 15
    
16.
Hofstraat K, van Brakel WH. Social stigma towards neglected tropical diseases: A systematic review. Int Health 2016; 8 (Suppl 1) : i53-70.  Back to cited text no. 16
    




 

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