Leprosy · Group on Chemotherapy for Leprosy Control, which recommended combined-drug regimens...

Report on

Leprosy

26–28 November 2002Geneva, Switzerland

www.who.int/tdr

TDR/SWG/02Original: English

Scientific Working Group

TDR/SWG/02

Report on Leprosy

Mailing address:TDRWorld Health Organization20, Avenue Appia1211 Geneva 27Switzerland

Street address:TDRCentre Casai53, Avenue Louis-Casai1216 Geneva Switzerland

Tel: (+41) 22-791-3725Fax: (+41) 22-791-4854E-mail: [email protected]: www.who.int/tdr

Report of the Scientific Working Groupmeeting on Leprosy

Geneva, 26–28 November, 2002

Report of the Scientif ic Working Group on Leprosy, 2002 • TDR/SWG/02 iii

TDR/SWG/02

Copyright © World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases (2003)All rights reserved.

The use of content from this health information product for all non-commercial education, training and information purposes is encouraged, including translation, quotation and reproduction, in any medium, but the content must not be changed and full acknowledgement of the source must be clearly stated. A copy of any resulting product with such content should be sent to TDR, World Health Organization, Avenue Appia, 1211 Geneva 27, Switzerland. TDR is a World Health Organization (WHO) executed UNDP/World Bank/World Health Organization Special Programme for Research and Training in Tropical Diseases.

This information product is not for sale. The use of any information or content whatsoever from it for publicity or advertising, or for any commercial or income-generating purpose, is strictly prohibited. No elements of this information product, in part or in whole, may be used to promote any specific individual, entity or product, in any manner whatsoever.

The designations employed and the presentation of material in this health information product, including maps and other illustra-tive materials, do not imply the expression of any opinion whatsoever on the part of WHO, including TDR, the authors or any parties cooperating in the production, concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delineation of frontiers and borders.

Mention or depiction of any specific product or commercial enterprise does not imply endorsement or recommendation by WHO, including TDR, the authors or any parties cooperating in the production, in preference to others of a similar nature not mentioned or depicted.

The views expressed in this health information product are those of the authors and do not necessarily reflect those of WHO, includ-ing TDR.

WHO, including TDR, and the authors of this health information product make no warranties or representations regarding the content, presentation, appearance, completeness or accuracy in any medium and shall not be held liable for any damages whatsoever as a result of its use or application. WHO, including TDR, reserves the right to make updates and changes without notice and accepts no liability for any errors or omissions in this regard. Any alteration to the original content brought about by display or access through different media is not the responsibility of WHO, including TDR, or the authors.

WHO, including TDR, and the authors accept no responsibility whatsoever for any inaccurate advice or information that is provided by sources reached via linkages or references to this health information product.

Design: Lisa SchwarbLayout by Inís: www.inis.ie

Report of the Scientif ic Working Group on Leprosy, 2002 • TDR/SWG/02 iii

1. Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

2. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

3. Rationale for the Scientific Working Group . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

4. Goals, objectives and expected outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

5. Partners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

6. Meeting report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7MAJOR CHALLENGES AND PRIORITY RESEARCH NEEDS . . . . . . . . . . . . . . . . . . . . . . . . . . .7ONGOING GLOBAL RESEARCH EFFORTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8RESEARCH OPPORTUNITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9

Transmission/diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9Nerve damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Research to improve integration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Cross-cutting issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

7. Next steps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Annex 1AGENDA: SCIENTIFIC WORKING GROUP ON LEPROSY . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

Annex 2LIST OF PARTICIPANTS: SCIENTIFIC WORKING GROUP ON LEPROSY . . . . . . . . . . . . . . . . . 17

Annex 3WORKING PAPER: SOCIAL, PSYCHOLOGICAL AND BEHAVIOURAL RESEARCH IN LEPROSY . . . 21

Annex 4WORKING PAPER: CHEMOTHERAPY AND CHEMOPROPHYLAXIS OF LEPROSY . . . . . . . . . . . . .27

Annex 5WORKING PAPER: LEPROSY – NEW OPPORTUNITIES IN BASIC SCIENCE . . . . . . . . . . . . . . . .35

Annex 6WORKING PAPER: THE IMPACT OF MULTIDRUG THERAPY ON TRENDS IN TRANSMISSION . . . . 41

Contents

Report of the Scientif ic Working Group on Leprosy, 2002 • TDR/SWG/02iv

Lepr

osy

Report of the Scientif ic Working Group on Leprosy, 2002 • TDR/SWG/02 1

Lepr

osy

Annex 7WORKING PAPER: CURRENT STATUS IN REACTIONS AND NERVE DAMAGE IN LEPROSY – WHAT NEXT? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47

Annex 8WORKING PAPER: ELIMINATION OF LEPROSY AS A PUBLIC HEALTH PROBLEM – CURRENT STATUS AND CHALLENGES AHEAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57

Figure 1. Global prevalence of leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58Figure 2. Global detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59Table 1. Global total years of life lost due to disability, years of life lost, and disability adjusted life years estimates, 1990 and 2000 . . . . . . . . . . . . . . . . . . . . . . . .59Table 2. Latest global leprosy situation as reported by 106 countries . . . . . . . . . . . . . . .60Table 3. Classification of new cases reported during 2000 . . . . . . . . . . . . . . . . . . . . . . 61Table 4. Proportion of children under 15 years old among new cases . . . . . . . . . . . . . . . 61Table 5. Proportion of disabilities among new cases . . . . . . . . . . . . . . . . . . . . . . . . . . 61Table 6. Annual detection trends in areas with repeated leprosy elimination campaigns . .63Figure 3. New leprosy cases detected through routine and MLEC, India, NLEP 1998-2002 . .63Figure 4. Hansen’s disease (leprosy) – reported cases by year, United States, 1970–2000 . .68

Annex 8aLATEST INFORMATION ON THE LEPROSY SITUATION AT COUNTRY LEVEL BY WHO REGION . . .73

Annex 9WORKING PAPER: ISSUES RELATED TO THE INTENSITY OF MYCOBACTERIUM LEPRAE TRANSMISSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79

Annex 10WORKING PAPER: VACCINES FOR LEPROSY AND OTHER MYCOBACTERIAL DISEASES – WHAT DO WE KNOW TODAY? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85

Table 1. Incidence of leprosy and protective efficacy of BCG by dose in a leprosy prevention trial in Chingleput, South India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .86Figure 1. Overall vaccine efficacy estimates during the second follow-up of a multi-arm leprosy vaccine trial in South India, 1998 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87Figure 2. Estimates of BCG efficacy against different forms of tuberculosis and leprosy from observational and experimental studies conducted worldwide . . . . . . . . . . . . . . . .88

Report of the Scientif ic Working Group on Leprosy, 2002 • TDR/SWG/02iv

Lepr

osy


Lepr

osy

1. Executive summary

In 1977, the World Health Organization (WHO) Expert Committee on Leprosy estimated the

global number of leprosy cases to be over 12 million. In 1981, WHO convened the Study

Group on Chemotherapy for Leprosy Control, which recommended combined-drug regimens

based on supervised intermittent administration of rifampicin for both multibacillary (MB) and

paucibacillary (PB) leprosy. Thanks to the implementation of this multidrug therapy (MDT),

substantial progress in leprosy control has been achieved and over 12 million cases had been

cured by 2002. However, to date there is no clear evidence of an impact of introduction of

MDT on the rate of detection of new cases. Approaches to address this question are impeded

by a lack of fundamental knowledge about the epidemiology of leprosy, the sources of infec-

tion, its precise mode of transmission and the importance of contact patterns.

Worldwide, and in spite of the dramatic impact of MDT on leprosy prevalence, 2-3 million

people are still living with deformities due to leprosy. As new cases remain at risk of develop-

ing nerve impairment, detecting, managing and understanding the mechanism(s) involved in

nerve damage remain a high priority for research programmes. Studies to date have not provid-

ed the optimal approaches needed to assure the prevention and management of nerve impair-

ment.

In most leprosy endemic countries, leprosy control activities have been integrated into the

general health services or are in the process of being integrated. Research priorities should

be directed at assessing and improving the quality of leprosy services in integrated settings,

addressing in particular issues of access, case detection, compliance, prevention of disability,

and referral services.

Multidisciplinary approaches that enhance research are essential to each research theme,

including social sciences approaches, which have been somewhat neglected recently as sci-

entists have focused more on the causative agent of leprosy. Collaboration with research-

ers in other topics should be actively encouraged. For example, nerve damage studies should

be linked with research in the neurosciences, while engagement of tuberculosis researchers

is of particular relevance in areas such as new drug exploration and vaccine and diagnostics

development. TDR has a specific role to play in sustaining the momentum in leprosy research

through capacity strengthening, promoting coordination of research proposals, and facilitating

funding opportunities for the identified research priorities.

The Scientific Working Group produced a clear consensus on the major possibilities for lep-

rosy research based on the expressed research needs from endemic countries and the current

Report of the Scientif ic Working Group on Leprosy, 2002 • TDR/SWG/022

Lepr

osy


Lepr

osy

research opportunities. The next step will be to develop these major research priorities into

detailed programmes and research protocols. Specific proposal development workshops will be

convened in 2003 to develop the proposals and protocols for research programmes in the iden-

tified areas: transmission/diagnostics, nerve damage, and integration into the general health

services.


Lepr

osy


Lepr

osy

2. Background

The World Health Organization (WHO) leprosy programme was responsible for the global

implementation of multidrug therapy (MDT) and for setting an elimination target, original-

ly for the year 2000. More recently, WHO formed a Global Alliance for the Elimination of

Leprosy (GAEL) with the aim of reaching the elimination target (less than 1 case per 10 000)

in all countries by 2005. A number of organizations have emphasized the need to sustain con-

trol activities after 2005, and to care for patients who are permanently disabled. A limited oper-

ational research component is included under the GAEL.

A number of other events preceded the convening of the Scientific Working Group (SWG)

on leprosy in 2002. These included the recent WHO Technical Advisory Group (TAG) held

in Brasilia, which reiterated its previous recommendations that the UNDP/World Bank/WHO

Special Programme for Research and Training in Tropical Diseases (WHO/TDR) should

maintain/focus its research efforts and address the research needs of leprosy control, including:

• development of strategies to ensure sustainability of control activities after the year 2005;

• development of partnerships necessary for maintaining a coordinated and effective research

programme;

• regeneration of dwindling research capacity in the leprosy disease endemic countries (DECs).

Another event was the TDR strategic review in 1999/2000, which concluded that TDR should

expand its analytical capacity, contribute more to global agenda setting, strengthen links with

control, and engage more in implementation research to ensure that new tools or systems are

rapidly adopted by control programmes.

The SWG was expected to take into account the results and recommendations for further

research as presented recently in the Report of the International Leprosy Association (ILA)

Technical Forum (International Journal of Leprosy and Other Mycobacterial Diseases, 2002,

70 [1 Suppl]:S1-62), and to take into consideration new research findings presented at the

International Leprosy Congress held in Salvador, Brazil, August 2002.


Lepr

osy


Lepr

osy

Current control measures have greatly reduced the prevalence of leprosy and are probably

reducing its transmission, although new case detection rates have remained relatively stable,

with only a slight downward trend, until recently. New control measures such as leprosy elim-

ination campaigns have been implemented, but their impact remains uncertain. There is a clear

need for additional innovative ways of increasing/facilitating case detection, for better under-

standing of leprosy transmission, and for better appreciating how to transfer leprosy control

activities into the general health services.

The global leprosy research effort has dwindled and many scientists have moved to TB

research. New discoveries, especially the sequencing of the Mycobacterium leprae, M. tuber-

culosis and other mycobacterial genomes, have opened up new opportunities for leprosy

research which remain to be fully exploited. Importantly, there is little research focus in sup-

port of the burning operational needs for ensuring sustainable leprosy control beyond 2005.

3. Rationale for the Scientific Working Group


Lepr

osy


Lepr

osy

The GOALS OF THE SWG were:• to recommend a leprosy research agenda and

demonstrate a clear rationale for TDR to con-tinue leprosy research, at least until the next SWG meeting in 2006/2007;

• to develop a rational, focused strategy for con-ducting leprosy research directly relevant to control needs, in partnership with the WHO lep-rosy unit, GAEL, and various research partners;

• to assess what new scientific opportunities exist to develop needed tools.

The OBJECTIVES OF THE SWG were:• to summarize the current status of leprosy con-

trol;

• to define the current/future research needs,

including with regard to deficiencies in knowl-edge and the effectiveness of currently availa-ble tools and strategies;

• to review leprosy research activities globally and identify scientific opportunities;

• to identify the gaps between needs and ongo-ing research efforts;

• to agree upon means of addressing the gaps, including strengthening existing and building new partnerships.

EXPECTED OUTCOMESThe SWG was expected to provide TDR with an overall strategy and scientific direction for lep-rosy research over the next five years, togeth-er with an agreed list of expected outcomes and potential impact(s) of this research programme.

4. Goals, objectives and expected outcomes


Lepr

osy


Lepr

osy

The WHO leprosy unit and partners in GAEL, including leprosy control programme manag-ers in the six high burden countries, were con-sidered essential partners for a successful SWG meeting. WHO inputs into the assessment of lep-rosy burden and leprosy vaccine/diagnostics research were also to be included, and major glo-bal research institutions involved, including the Indian Council of Medical Research, Oswaldo Cruz Foundation (FIOCRUZ), University of Colorado, Institut Pasteur, Aberdeen University, Royal Tropical Institute, Erasmus University, London School of Hygiene and Tropical Medicine, and various leprosy nongovernmental organizations (NGOs).

5. Partners


Lepr

osy


Lepr

osy

MAJOR CHALLENGES AND PRIORITY RESEARCH NEEDS

MDT has reduced the global prevalence of lep-rosy enormously and cured millions of patients, and in some countries case detection rates have shown a progressive decline. However, review of available data on trends in case detection rates shows no evidence of an impact associated with the introduction of MDT, and these rates remain high in some countries. The extent to which the figures provide a measure of leprosy transmis-sion is unclear since case detection rates are influenced by multiple and complex operation-al factors, including the inadequacies of diagnos-ing patients based on presence of skin lesions. Present field diagnostic methods sometimes lead to substantial over-diagnosis of a portion of pau-cibacillary patients; they also lead to underdiag-nosis, especially of early multibacillary patients. Misdiagnosis and underdiagnosis of leprosy is likely to increase in decentralized and integrated leprosy control services, where staff involved in diagnosis of leprosy are less experienced.

Simulation models based on case detection data suggest that, under current circumstances, there is little likelihood of any dramatic downturn in the number of new cases over the next dec-ade. Lessons from other diseases suggest there is a real danger that failure to meet expectations of reduced patient numbers will have a signifi-cant negative impact on future prospects for lep-rosy control and its integration into the general health services. The problems are compounded by lack of fundamental knowledge about the epi-demiology of leprosy, the sources of infection, the precise mode of transmission, and the impor-tance of contact patterns. To approach the goal of eradication of leprosy, and perhaps even sus-tain current successes, a new need is to identify new intervention strategies that target reduction of transmission. Given the difficulties of measur-

ing transmission based solely on new case detec-tion rates, there is a need for objective measures that better reflect transmission.

Other major research challenges and needs include:

• Understanding the contribution of operation-al factors to delayed diagnosis and initiation of treatment, and of contagiousness prior to development of symptoms.

• Developing more specific diagnostic tools for field application.

• Investigating novel intervention strategies such as chemoprophylaxis and immunoproph-ylaxis in terms of ability to interrupt trans-mission, cost effectiveness, and compatibility with health systems and local cultural consid-erations, particularly focusing on defined high risk groups or areas.

• Using epidemiological and community based approaches to identify high risk groups from an operational and intervention perspective.

• Developing tests to accurately identify per-sons who are in contact with leprosy and have become infected, in order to understand trans-mission. Several tests, based on combined measurement of humoral and cellular immune responses and in some instances on direct evi-dence of presence of bacteria or their products, are under development. These tests need to be evaluated in the context of carefully defined epidemiological questions.

• Developing approaches to distinguish different strains of M. leprae in order to help understand its transmission patterns. In an analogous way, methods used to distinguish different strains of mycobacteria were very important in under-standing the transmission patterns of tubercu-losis.

• Exploitation of existing data and generation of improved data sets in order to enhance the use of mathematical models to gain better insight into the dynamics of leprosy infection, predict

6. Meeting report


Lepr

osy


Lepr

osy

the effect of different interventions, and pro-vide an important advocacy tool.

Nerve function impairment and reactions repre-sent major challenges and priorities, both for pre-vention of infection and development of effective treatments. Nerve function impairment, which limits a person’s activities and affects his/her par-ticipation in society, is a result of infection with M. leprae and the host’s response to this infec-tion; it can be acutely associated with reaction-al episodes, either before diagnosis of leprosy or during MDT treatment. The proportion of new cases with evidence of nerve function impair-ment at diagnosis varies considerably between countries and in many situations is greater than 20% of all new cases. The risk of reactions dur-ing MDT treatment is low in paucibacillary (PB) patients but can be as high as 50-60% in multi-bacillary (MB) patients with pre-existing nerve damage. Impairment of sensory, motor and auto-nomic nerve function leads to a progressive proc-ess of recurrent trauma, tissue damage and tissue loss affecting the eyes, hands and feet. The con-sequences of leprosy have a profound impact on individual patients, their families and communi-ties and are associated with much of the stigma associated with the disease.

Nerve function impairment and reactions repre-sent major challenges and priorities – both for prevention and development of effective treat-ments.

ONGOING GLOBAL RESEARCH EFFORTS

Research on the epidemiology of leprosy is lim-ited by the problems associated with a low inci-dence of disease, a long incubation time, and a lack of relevant tools. Some studies to evaluate the effect of chemoprophylaxis are under way, e.g. in Bangladesh, India and Indonesia, while in

Cuba, treatment of serologically-positive contacts is routine practice. Immunoprophylaxis studies in South India and Malawi are being followed up, and the effect of repeat BCG vaccination is being assessed in Brazilian schoolchildren.

Serological tests for antibodies to M. leprae phe-nolic glycolipid –1 (PGL-1) have been extensive-ly characterized in endemic settings, and rapid simple assays are now being evaluated in the field. Attempts are under way to identify antigens suitable for use as improved skin test reagents; these are undergoing initial evaluation in Nepal and Brazil. Recombinant proteins and synthetic peptides are also being investigated as potentially specific antigens for use in blood-based tests to measure T cell responses to M. leprae as an indi-cator of infection.

Efforts are under way in a few laboratories to identify genetic polymorphisms as the basis for development of strain typing systems for M. lep-rae. Variations in short tandem repeat loci appear particularly promising.

A range of research efforts addressing nerve dam-age are currently being undertaken. Although largely uncoordinated in the past, recent devel-opments have led to more coordination of these efforts. Work in progress includes, in the basic sciences, study of the mechanisms of neurotro-pism and the pathogenesis of nerve damage, while a number of epidemiological studies have provid-ed important understanding of the risk factors for nerve function impairment and reactions. Several clinical trials of interventions for prevention and treatment of reactions are nearing completion in India, Bangladesh and Nepal, based on new reg-imens and new drugs, while a major research initiative, INFIR, is in progress using a multidis-ciplinary approach to address the pathogenesis of nerve damage and reactions, novel treatments, recurrent reactions and delay in diagnosis.


Lepr

osy


Lepr

osy

RESEARCH OPPORTUNITIES

The availability of M. leprae and other myco-bacterial genome sequences provides important opportunities for identifying novel M. leprae-specific antigens that can be used to develop improved tests for infection. This sequence infor-mation is also central to prospects for developing molecular epidemiology approaches for lepro-sy. In addition, leprosy research is well placed to benefit from the rapid advances in post-genome technologies such as microarrays and bioinfor-matics.

Research on transmission is particularly time-ly given the current epidemiological situation in which MDT is reducing the prevalence of lepro-sy but leaving a sustained level of new cases.

A specific research opportunity to explore neu-rotropism in leprosy is provided by the genome project, while opportunities to investigate the basic mechanism(s) of nerve damage in lepro-sy are provided by new Schwann cell models of M. leprae infection. A new generation of immu-noregulatory drugs and TNF-α inhibitors is pro-viding new therapeutic opportunities, while the development of standardized outcome measures from the recent clinical trials for nerve function and reactions, and measurements of activities and participation, are providing opportunities for new clinical studies.

The TDR Scientific Working Group on Leprosy identified four specific research priorities – transmission, diagnostics, nerve damage and reactions, and the integration of leprosy con-trol activities. A number of issues are relevant to each of these research priorities.

Transmission/diagnostics

To sustain current successes and to approach the

goal of eradication of leprosy, there is a need to identify new intervention strategies that comple-ment MDT by targeting reduction of transmission.

Research priorities

1. Evaluation of the impact on leprosy trans-mission of chemoprophylaxis and immuno-prophylaxis with vaccines of proven efficacy (BCG and ICRC [an Indian version of BCG]). Controlled trials should include evaluation of relevant objective tests for infection in addi-tion to standardized case detection. Data from ongoing trials and programmes should be used to strengthen expertise in modelling approaches to understand leprosy transmis-sion and for scenario analysis.

2a. Evaluation of use of PGL-1 serology as a marker for high risk groups suitable for chem-oprophylaxis or other interventions.

2b. Assessment of the utility of skin test reagents based on fractionated M. leprae or recom-binant proteins as an epidemiological tool to identify infected individuals. Comparison of recombinant M. leprae-specific proteins and synthetic peptides with blood-based tests involving measurement of T cell respons-es, e.g. gamma interferon production, with respect to sensitivity, specificity and opera-tional feasibility.

2c. Further improvement of the usefulness of polymerase chain reaction (PCR) detection of M. leprae, and development and valida-tion of strain-typing systems for M. leprae. This should include generation of genome sequence data from additional M. leprae iso-lates, coordination between different research groups working globally, and testing of assays in well-defined epidemiological settings.

3. Detailed epidemiological studies and analyses of the contributions of different exposure pat-terns to the development of disease and posi-tivity in tests for infection.


Lepr

osy


Lepr

osy

Funding strategiesTDR is well placed to coordinate a proposal for a major multidisciplinary project on lepro-sy transmission which would be appropriate for external funding. Such a proposal would require initial funding of collaborative workshops to bring together partners from different countries and disciplines for formulating trial designs and standardizing relevant assays and reagents.

TDR comparative advantageStudies of leprosy transmission should be carried out in different geographic settings and should involve a range of expertise from bench scientists and clinicians to epidemiologists, programme managers, economists and social scientists. TDR is uniquely placed to bridge interactions between partners in developed and developing countries and to bring together the appropriate spectrum of expertise.

The development and application of tests for infection provide opportunities for scientific col-laborations and research strengthening in the key disciplines of molecular biology, bioinformatics, immunology and epidemiology. TDR is the ideal coordinator for such activities.

Findings from the proposed research programme will have obvious and immediate implications for implementation and control policies. Standing at the interface of research and control, TDR is well-placed to facilitate such progress.

TDR has a key role to play in sustaining momen-tum in leprosy research by encouraging the inter-ests of basic scientists and motivating control personnel. Research on leprosy transmission addresses both of these aspects.

Nerve damage

Although MDT has had a dramatic impact on prevalence of leprosy, still 2 to 3 million people

worldwide have deformities due to the disease. In addition, in many parts of the world there has been little impact on the rate of detection of new cases, and these new cases remain at risk of developing nerve impairment. Thus detecting, managing and understanding the mechanisms involved in nerve damage remain a high priori-ty. Trials of prophylaxis and treatment of nerve damage have not provided optimal approach-es for the prevention and management of nerve impairment. Therefore a combination of clini-cal and epidemiological research and mechanis-tic studies is required for the identification of risk factors, management, and prevention of nerve damage. We recommend the following areas as priorities for research.

Research priorities

1. Investigation of the role of prophylaxis with steroids in preventing nerve damage.

2. Development of methods to identify patients at high risk of going into reaction.

3. Research on the management of patients at high risk.

4. Research on new treatments for nerve damage, including new steroid regimens, new immu-nosuppressive drugs, and specific inhibitors of cytokine or signalling pathways.

5. Immunopathological and/or cell culture approaches to understanding the interaction between M. leprae and host cells (Schwann cells, macrophages, dendritic cells) at the molecular level. Such studies might lead to the development of:

- Improved understanding of the mechanism of action of steroids;

- New markers of nerve damage;

- New tools for the prevention of nerve damage;

- Improved treatments for nerve damage and nerve regeneration.


Lepr

osy


Lepr

osy

Funding strategyThis topic is appropriate for seed funding by TDR and of potential interest to several NGOs.

Research to improve integration

In most leprosy endemic countries, leprosy con-trol activities have been integrated into the gen-eral health services or are in the process of being integrated.

Major advantages of this integration are increased accessibility of diagnosis and treat-ment, decreased stigma, and increased sustaina-bility and cost-effectiveness. However, there is concern that development of integrated servic-es will lead to deterioration in quality of care for leprosy patients. Regimens that shorten the dura-tion of treatment and are uniform for all patients will considerably simplify administration of treatment through the general health services.

Research priorities

1. Assessment and improvement of quali-ty of leprosy services in integrated settings, addressing, in particular, issues of access, case detection, compliance, prevention of disabili-ty, and referral services.

2. Assessment of new drug regimens for use in integrated settings. The proposed multicentre study on a six-month uniform MDT regimen for all leprosy patients addresses the need for a simplified treatment scheme.

3. Assessment of the current situation with regard to rifampicin resistance.

Funding strategy Co-funding for the above three research areas should be sought through various NGOs and multilateral funding agencies.

Cross-cutting issues

The TDR Scientific Working Group on Leprosy identified four specific research priorities – trans-mission, diagnostics, nerve damage and reac-tions, and the integration of leprosy control activities. A number of issues are relevant to each of these priorities, for which important research opportunities, underpinned by post-genomics research, were provide Gd by sequencing of the M. leprae genome. Multidisciplinary approach-es that enhance research are essential to each of the research themes, including social sciences approaches, which have been somewhat neglect-ed recently as scientists have focused more on the causative agent of the disease. Collaboration with researchers in related topics should be actively encouraged. For example, nerve dam-age studies should be linked with research in the neurosciences, while collaboration with tuber-culosis researchers is of particular relevance in areas such as new drug exploration and vaccine and diagnostics development. It is recognized that HIV may have a potential impact on each area of research. TDR has a specific role to play in sustaining the momentum in leprosy research through capacity strengthening, promoting coor-dination of research proposals, and facilitating funding opportunities for each of the identified research priorities.


Lepr

osy


Lepr

osy

The Scientific Working Group achieved a very clear consensus on the major possibilities for lep-rosy research based on the expressed research needs from endemic countries and the current research opportunities. The next step is to devel-op these major research priorities into detailed programmes and research protocols. Specific

workshops will be convened in 2003 to devel-op the proposals and protocols for research programmes in the four areas: transmission, diag-nostics, nerve damage, integration. Draft research protocols will be prepared by mid-2003 and finalized for submission to funding agencies by the end of 2003.

Time frame: November 2002 . . . SWG January 2003 . . . SWG report Mid-2003 . . . Workshops and draft proposals End-2003 . . . Proposals submitted to funding agencies

7. Next steps


Lepr

osy


Lepr

osy

Annex 1 AGENDA: Scientific Working Group on Leprosy

Report of the Scientif ic Working Group on Leprosy, 2002 • TDR/SWG/0214 Report of the Scientif ic Working Group on Leprosy, 2002 • TDR/SWG/02 15

Salle A, WHO/HQ, Geneva, Switzerland, 26-28 November 2002

Day 1 (Tuesday 26 November 2002)

09:00-09:30 Welcome and introductions C Morel, Director CPE

Objectives and expected outcomes H Remme

09:30-10:15 TDR’s research strategy in 2002-2005 C Morel

10:15-10:30 Discussion All

10:30-10:45 Coffee

10:45-11:15 Leprosy control as seen by the endemic countries Kyaw Nyunt Sein

11:15-11:45 Leprosy control as seen by ILEP/ILA WCS Smith

11:45-12:00 Discussion

12:00-12:20 Research needs for ensuring leprosy control beyond 2005 as seen by TAG

M Becx

12:20-12:40 Present strategic directions for leprosy research in TDR H Engers


13:00-14:00 Lunch

14:00-14:30 Mycobacterial genomics S. Cole


14:45-15:15 Chemotherapy and chemoprophylaxis of leprosy Baohong JI


15:30-15:45 Tea

15:45-16:15 Leprosy transmission and epidemiological trends P Klatser


16:30-17:00 Eradication of leprosy? Future research needs J Krahenbuhl


18:00 Cocktail at WHO


TDR offices, Centre Casai, rooms 4115-4117, 53 avenue Louis-Casai

Day 2 (Wednesday 27 November 2002)

Three break-out groups with presentations/discussion/recommendations (09:00 to 12:30; 14:00 to 17:30)(each presenter listed after each topic for discussion has 15 minutes to address the “hot” issues and make suggestions/recommendations)Note: Cross-cutting issues – RCS capacity building needs and research funding challenges – are to be addressed in all three groups

Room 1 Chair: D Young. Transmission of leprosy – how is it transmitted? (P Brennan). The impact of MDT on trends in transmission (A Meima). The evidence for/against the role of sub-clinical infections. Progress in developing a test for infection (P Klatser). Chemoprophylaxis (Baohong Ji). Exit strategy for leprosy research – eradication? (all).

Room 2 Chair: E Pereira Sampaio. Pathogenesis – prevention of nerve damage (C Pessolani). Disability management (WCS Smith). Vaccines for leprosy and other mycobacterial diseases – what do we know today? (MD Gupte). What do we need to know? (T Ottenhoff). Genomics and M. leprae: molecular advances and expected outcomes (T Gillis).

Room 3 Chair: M Becx-Bleumink. Implementation research in leprosy. Analysis of the constraints facing leprosy control (SK Noordeen). What are/should be the goals of field research? (D Lockwood). Integration? (E Bizuneh). Sustainability? (V Katoch).

WHO Headquarters, Salle A

Day 3 (Thursday 28 November 2002)

Presentation of group reports; discussion; draft recommendationsRapporteur’s presentations of the three group reports and discussions:

08:30-09:15 Group 1: Transmission/test for infection/exit strategy


09:35-10:20 Group 2: Pathogenesis/disability management/prevention


10:40-11:00 Coffee

11:00-11:45 Group 3: Implementation research/constraints/sustainability


12:05-12:30 General discussion

12:30-14:00 Lunch

General discussion and summing up; recommendations and action items:

14:30-15:45 General discussion (on points identified by chairpersons/rapporteurs of the three groups)

15:45-16:00 Tea

16:00-17:30 Draft recommendations and action items

17:30 Concluding remarks

Chair of meeting


Lepr

osy

WHO Headquarters, Salle A

Day 4 (Friday 29 November 2002)

Subgroup follow-up (Dr Marijke Becx-Bleumink, Professor WCS Smith, Dr Douglas B Young)

TDR/TAG subgroup to finalize draft report and brief directors

Lunch

SWG meeting concluded

Background documents provided to the participants

• WHO Expert Committee on Leprosy (7th Report)

• Report on Third Meeting of the WHO Technical Advisory Group on Elimination of Leprosy, Brasilia, 1&2 February 2002

• TDR strategy for 2000-2005

• Strategic direction for research on leprosy

• Strategic emphases for tropical diseases research: article and matrix

• Report of the International Leprosy Association Technical Forum, Paris, France, 22-28 February 2002


Lepr

osy

Annex 2 LIST OF PARTICIPANTS: Scientific Working Group on Leprosy


Temporary advisers

Dr Jens AAGAARD-HANSEN, Danish Bilharziasis Laboratory, Jaegersborg Allé 1D, DK-2920 Charlottenlund, Denmark. Tel: +45 77 32 77 84 Fax: +45 77 32 77 33 E-mail: [email protected]

Dr AO AWE, Department of Public Health, National TBL Control Programme, Federal Ministry of Health, Abuja, Nigeria. Tel: +234 1 269 3018Fax: +234 1 68 40 91E-mail: [email protected]

Dr Jaya Prasad BARAL, Department of Health Services, Ministry of Health, His Majesty’s Government of Nepal, Teku, Kathmandu, Népal. Tel: +977 1 262009 Fax: +977 1 248535E-mail: [email protected]

Dr Marijke BECX-BLEUMINK, Royal Netherlands Tuberculosis Association,Riouwstraat 7, PO Box 146, 2501 The Hague, The Netherlands. Tel: +31 70 416 7222Fax: +31 70 358 4004E-mail: [email protected]

Dr Elizabeth BIZUNEH, ALERT, PO Box 165, Addis Ababa, Ethiopia. Tel: +251 1712552 Fax: +251 1711390E-mail: [email protected]

Professor Patrick J BRENNAN, Department of Microbiology, B116 Microbiology Building, Colorado State University, Fort Collins, CO 80523-1677, USA. Tel: +1 970 491 6136 Fax: +1 970 491 1815E-mail: [email protected]

Dr Stewart Thomas COLE, Institut Pasteur, Unité de Genetique Moleculaire Bactérienne, 28 rue du Docteur Roux, F-75724 Cedex 15. Tel: +33 1 45 68 84 49 Fax: +33 1 40 61 35 83E-mail: [email protected]

Dr MJ COLSTON, (deceased) Division of Mycobacterial Research, National Institute for Medical Research, Medical Research Council, The Ridgeway, Mill Hill, GB-London NW7 1AA. Tel: +44 181 959 3666 (ext. 2353/2354)Fax: +44 181 913 8528E-mail: [email protected]

Professor Hazel Marguerite DOCKRELL, London School of Hygiene and Tropical Medicine, Infectious and Tropical Diseases Immunology Unit, Keppel Street, London, United Kingdom. Tel: +44 207 927 2466Fax: +44 207 637 4314E-mail: [email protected]

Dr Thomas P GILLIS, Molecular Biology Research, National Hansen’s Disease Programs Laboratory, Louisiana State University School of Veterinary Medicine, Skip Bertman Dr, Baton Rouge, LA 70803, United States of America. Tel: +1 225-578-9836Fax: +1 225-578-9856E-mail: [email protected]

Dr Vera Lucia GOMES DE ANDRADE, Rua General Glicério 82/704, Laranjeiras, Rio de Janeiro, CEP 22.245-120, Brésil. Tel: +55 21 2558 2194Fax: +55 21 534 3895E-mail: [email protected]

Dr MD GUPTE, National Institute of Epidemiology, Indian Council of Medical Research, Post Box 2577, Mayor VR Ramanathan Road, Chetpet, Chennai 600 031, India.Tel: +91 44 8265308 / 8261642 Fax: +91 44 8264963E-mail [email protected]

Professor Baohong JI, Bacteriologie et Hygiene, Faculte de Medecine Pitie-Salpetriere, 91 boulevard de l’Hopital, 75634 Paris, Cedex 13, France. Tel: +33 140 77 97 46Fax: +33 145 82 75 77E-mail: [email protected]

Dr Vishwa Mohn KATOCH, Central JALMA Institute for Leprosy (ICMR), PO Box 101, Taj Ganj, Agra-282 001, India.Tel: +91 562 331 756Fax: +91 562 331 755E-mail: [email protected]

Dr Paul Richard KLATSER, Royal Tropical Institute, NH Swellengrebel Laboratory of Tropical Hygiene, Meibergdreef 39, Amsterdam, NL-1105, The Netherlands.Tel: +31 20 566 5441Fax: +31 20 697 1841E-mail: [email protected]

Dr James L KRAHENBUHL, Laboratory Research Branch, National Hansen’s Disease Programs Laboratory, Louisiana State University School of Veterinary Medicine, Skip Bertman Dr, Baton Rouge, LA 70803 United States of America. Tel: +1 225 578 9845Fax: +1 225 578 9856E-mail: [email protected]


Dr Ashok KUMAR, Directorate of Health Services, Nirman Bhawan, New Delhi 110011, India. Tel: +91 11 331 7804Fax: +91 11 331 8607E-mail: [email protected]

Dr Diana LOCKWOOD, Clinical Research Unit, Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Tel: +44 171 927 2457Fax: +44 171 637 4314; E-mail: [email protected]

Dr Celina Maria Turchi MARTELLI, Federal University of Goias Instituto de Patologia Tropical e Saude Publica, Sala 405, Rua Delenda Rezende de Mello, Goiania, GO, Brazil. Tel: +55 62 202 0605Fax: +55 62 261 6389 or 202 3066E-mail [email protected]

Dr Abraham MEIMA, Erasmus University Rotterdam, Department of Public Health Medical Decision Sciences, PO Box 1738, Rotterdam, NL-3000, The Netherlands.E-mail: [email protected]

Dr Elizabeth MOREIRA DOS SANTOS, DENSP/FIOCRUZ, Av. Brasil 4365 Manguinhos, Cx postal 926, CEP 21045-900, Rio de Janeiro, Brazil. Tel: +55 21 2590 4712Fax: +55 21 2590 9741E-mail: [email protected]

Dr Alcino NDEVE, Ministry of Health, c/o WHO Representative, CP 377, Maputo, Mozambique. Tel: +258 1 49 90 55Fax: +258 1 49 19 90E-mail: [email protected](unable to attend)

Dr SK NOORDEEN, Leprosy Elimination Alliance, 1-A, KG Valencia, 57-First Main Road, Gandhinagar, Chennai 600020, India (9 Anna Avenue, B. V. Nagar Extension, Chennai 600 020). Tel: +91 44 4456337Fax: +91 44 4456338E-mail: [email protected]

Dr Kin Than OO, Central Health Education Bureau, Department of Health Planning, Ministry of Health, 27 Pyidaungsu Yeiktha Road, Dagon,Yangon, Union of Myanmar.Tel: +95 1 29 29 01Fax: +95 1 29 05 81

Dr Tom HM OTTENHOFF, University Hospital Leiden, Department of Immunohaematology and Bloodbank, PO Box 9600, Leiden, Rijnsburgerweg 10, Building 1, E3-Q, NL-2300 RC, The Netherlands. Tel: +31 71 526 5128Fax: +31 71 521 6751E-mail: [email protected]

Dr Gerson PEREIRA, Ministry of Health, Esplanada dos Ministérios, Bl. G – 5° andar, 70058-900 Brasilia DF, Brazil. Tel: +55 61 321 1922 Fax: +55 61 312 6550E-mail: [email protected] (unable to attend)

Dr Elisabeth PEREIRA SAMPAIO, Fundação Oswaldo Cruz, Departamento de Hanseniase, Av. Brasil, 4365 – Manguinhos, 21045-900 Rio de Janeiro, Brasil.Tel: +55 21 2598-4442Fax: +55 21 2270-9997E-mail: [email protected]

Dr Maria Cristina Vidal PESSOLANI, Fundacao Oswaldo Cruz, Hanseniase Leprosy Laboratory, Av. Brasil, 4365 Manguinhos, 21045-900 Caixa postal, 926 Rio de Janeiro, Brasil. Tel: +55 21 2709997Fax: +55 21 2709997E-mail: [email protected]

Dr Euzenir Nunes SARNO, Research and Technological Development, Oswaldo Cruz Foundation, Ministério da Saúde, Av. Brasil 4365, Manguinhos, Pavilhão Mourisco S.105, 21045-900 Rio de Janeiro, Brazil. Tel: +55 21 2590 4712Fax: +55 21 2590 9741E-mail: [email protected] (unable to attend)

Dr Kyaw Nyunt SEIN, Leprosy Control Programme, Department of Health,36 Theinbyu Road, Yangon, Myanmar. c/o WHO Representative Tel: 951 212606;Fax: +95 1 21 26 05, E-mail: [email protected] or [email protected]

Professor WCS SMITH, Department of Public Health, Medical School, Polwarth Building, University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD, United Kingdom. Tel: +44 1224 553802Fax: +44 1224 662994E-mail [email protected]


Lepr

osy

Dr Douglas B YOUNG, Centre for Molecular Microbiology and Infection, Flowers Building, Imperial College, London SW7 2AZ, United Kingdom. Tel: +44 20 7594 3962Fax: +44 20 7594 3095E-mail: [email protected]

Observer

Dr Richard SKOLNICK, Director, Center for Global Health, George Washington University, 2175 k. Street, Suite 810, Washington, DC 20037. Tel: +1 703-264-9063 E-mail:[email protected] (unable to attend)

Secretariat

Dr Carlos Morel, Director, TDR

Mr Erik Blas, Programme Manager, TDR

Dr Howard Engers, Leprosy Research Coordinator, TDR

Dr Gomes Melba, Functional Coordinator (a.i.), Interven-tion development and implementation research, TDR

Dr Ayo Oduola, Functional Coordinator, Basic and Strategic Research, TDR

Dr Hans Remme, Disease Research Strategy Coordinator, TDR

Dr Rob Ridley, Functional Coordinator, Product Research and Development, TDR

Dr Fabio Zicker, Functional Coordinator, Research Capability Strengthening, TDR

Dr Nevio Zagaria, Coordinator, Strategy Development and Monitoring for Eradication and Elimination, CPE

Dr Denis Daumerie, CPE/CEE (Leprosy group)

Dr Myo Thet Htoon, CPE/CEE (Leprosy group)

Dr Vijaykumar Pannikar, CPE/CEE (Leprosy group)

Dr Clovis Lombardi, PAHO/WHO Regional Advisor for Leprosy


Lepr

osy

Annex 3 WORKING PAPER: Social, psychological and behavioural research in leprosy


SOCIAL, PSYCHOLOGICAL AND BEHAVIOURALRESEARCH IN LEPROSY

W Cairns S Smith, Peter G NichollsDepartment of Public Health, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.

INTRODUCTION

Social, behavioural and psychological aspects of leprosy and its control have been relatively neglect-ed areas in terms of research. However, in the past five years there have been clear signs of a change with more research being undertaken, more publica-tions in the field and a greater emphasis in funding research using these methods. Leprosy Review com-missioned a special issue (1) on the topic of social aspects in December 2000. There were workshops, papers, posters and seminars addressing research using social, behavioural and psychological meth-ods throughout the International Leprosy Congress in Brazil, 2002.

The use of social and behavioural research methods is relevant across the spectrum of leprosy control activities and rehabilitation. This research approach is relevant to the issues of information, education and communication, and awareness of first symp-toms. The approach is important in addressing help-seeking behaviours and contact with health care providers. There are psychological and behavioural dimensions to communicating the diagnosis and relationships with the family and community. Social behaviour is also relevant to adherence with treat-ment and prevention of disability and rehabilitation. Recent work is also focusing on issues of stigma and community behaviours and attitudes.

This paper selects areas where social, psycholog-ical and behavioural research methods can make a particular contribution: community awareness and attitudes to leprosy, first symptoms, help-seek-ing behaviour and delay in presentation, adher-ence with treatment, stigma and stigmatization, and socioeconomic aspects of rehabilitation. The follow-ing sections draw attention to what is known from research, highlighting the relevance and impor-tance, and raise questions as to whether more needs to be done in implementing knowledge or further research.

COMMUNITY AWARENESS AND ATTITUDES TO LEPROSY

Information, education and communication (IEC) has been a key part of leprosy control activities for decades. Much of this activity has been conducted on a limited evidence base and there has little robust work on evaluating such interventions. The BBC Marshall Plan of the Mind Trust (MPM) initiatives in the last five years have been important develop-ments that have also been evaluated in depth. The main objective of the evaluation was to gauge the changes in knowledge, attitudes and perceptions of the community regarding leprosy at the end of the year long media campaign. This whole aspect of leprosy control activities is critical to early case detection, early symptom reporting, and for chang-ing community attitudes to leprosy and those affect-ed by leprosy.

Social marketing approaches in leprosy have been developed and demonstrated to be effective in coun-tries such as Sri Lanka (2). The programme encour-ages people with suspicious skin lesions to seek diagnosis and care, teaches health care providers to recognize leprosy and refer cases for treatment, and helps the general public to understand that lep-rosy is just a normal disease. The socially market-ed product is multidrug therapy. This approach has changed community awareness, attitudes to leprosy, and improved early detection and treatment.

FIRST SYMPTOMS, HELP SEEKING BEHAVIOUR AND DELAY IN PRESENTATION

Over the past five years, a programme of research funded through the International Federation of Anti-leprosy Associations (ILEP) has used qual-itative methods to explore delay in presentation, patient pathways to health care, and help-seeking behaviour. This work has included centres in India, Bangladesh, Malawi, Brazil and Paraguay. Similar research has been conducted in Nepal and Nigeria. The work shows important country and regional variations demonstrating that the factors are culture and context specific and that the solutions need to be similarly context specific. The work has lead to the production of guidelines to help leprosy control staff explore delay in presentation and start of treat-ment, which has consequences for transmission of leprosy and in addressing unacceptably high rates of impairments (3).

Perceived stigma associated with the diagnosis of leprosy may threaten self-esteem, security, identities and life chances, leading to concealment of the diag-


nosis. In India, Bharath et al (4) have shown an asso-ciation with psychiatric morbidity. In South Africa, Scott (5) reported that responses to the leprosy diag-nosis included feelings of rejection, worthlessness, guilt, confusion, fear, grief and anger, with 11 of 30 patients interviewed reporting suicidal thoughts. In Brazil, De Oliveira (6) reported the response to diagnosis to include fear, disgust, loneliness, grief, aggressiveness, anger, family and social rejection. These reports draw attention to the potential for a significant psychological impact on people affected by leprosy. Is this an area sufficiently recognized or managed? What are the implications? For example, where the disease is suspected or diagnosed, this may restrict help-seeking actions and so contribute to delay.

Angel and Thoits (7) present a framework describ-ing the impact of culture on the process of symptom recognition, labelling and help-seeking behaviour. First they suggest that people inherit from their cul-tures structured vocabularies of health and illness which limit the possibilities for the interpretation of physical and psychological states and struc-ture help-seeking options. Second, they assert that these concepts of health and illness tend to be “over-learned”, to the extent that they acquire the status of unquestioned objective reality. Finally they suggest that the labels attached to symptoms or illnesses influence their evaluation and determine the actions taken in response to perceived deviations from physical or emotional normality. Thus the response to a disorder may be dependent on prior evaluation concerning its nature, severity, chronicity, cause, contagiousness, personal responsibility, prognosis, futility etc., with the consequence that people may delay seeking treatment for culturally undesirable disorders.

The literature includes many examples suggesting that such processes affect the response to leprosy. Neylan et al in Thailand (8) report that the response to illness differs according to demographic and per-sonal factors, to physical and social factors, and to illness-related factors, specifically pain, disfigure-ment and stigma. Leprosy was perceived and expe-rienced as a series of acute disorders not necessarily related to one another. The various theories of ill-ness were instrumental in directing treatment choic-es that included indigenous healing practices. Other authors found similar complexity in responses to leprosy in Nigeria (9), Sierra Leone (10), Pakistan (11), Senegal (12) and Indonesia (13). Becx-Bleumink (14) highlights the implications for Ethiopia. She concluded that delay in presentation was a continu-ing problem, indicating that there are many undi-agnosed patients in the community. Although the

programme had been effective with respect to treat-ment, it had not been effective in regard to case detection.

Research questions:

1. What are the IEC and organizational interven-tions that have proven to be most effective in addressing delay/encouraging early detection? How can genuine community participation, rather than tolerance, be achieved? Where it has been achieved, what difference has it made?

2. Is there a more appropriate indicator than Grade 2 disability to draw attention to delay in presentation – i.e. a direct reflection of delay or a threshold value? Grade 2 disability effec-tively sanctions delays where there is no visible impairment.

3. What is the extent of the psychological impact of leprosy? Is there sufficient awareness of the social and psychological impact on the affected person? How should this be addressed?

ADHERENCE WITH TREATMENT

Social and psychological research and models of behaviour have now been applied to issues of treat-ment compliance and adherence. This has important implications for treatment completion rates and lep-rosy control programme quality.

Anandaraj (15) states that default in leprosy treat-ment is a reflection of underlying emotional, social and cultural resistance which go undetected and hence neglected. Thus the patient continues in a state of ill-health. He/she patient may spread not only the disease but also the negative attitude towards treatment. These factors counter efforts to control the disease and require attention. Anandaraj found that the most common reason stated for default was that individuals were not convinced of their disease (diagnosis). Low levels of awareness were associated with low motivation for cure.

From his work in Indonesia, Elissen (13) recognized that, while many patients presented voluntarily for treatment, there were still causes for concern about their social well-being. He observed a widespread sense of shame and strong self-discrimination, even among those whose symptoms had never been vis-ible. This was illustrated by using different names, by visiting different clinics, and by giving wrong addresses. While accepting the diagnosis of leprosy, they gave their disease a vague and general name. Elissen concluded that something was lacking in the communication between patient and health work-er. Treatment should extend beyond prevention


and cure to alleviation of fear. Mull has similar find-ings about the inadequacy of the communication between staff and patient in Pakistan.

Heynders (16) reviews published reports finding poorer adherence among women, suggesting prob-lems of access/freedom of movement. However people who travel long distances from choice are found to be compliant. From her work in Nepal, Heynders found none of the variables assessed at registration to have value as risk factors for default. She did find that late return for the first three return visits was a risk factor for default. She then iden-tified the need for prospective research to explore why some people default after 3-7 visits. What are the experiences that result in their default? She also draws attention to the very short time available to communicate messages that might prevent default-ing. Her conclusion stresses the complexity of com-pliance. Is the patient able to comply? How does the patient weigh the need to comply with other pres-sures they face in everyday life? Of basic importance is how the individual understands their disease and its treatment.

STIGMA AND STIGMATIZATION

In 1981, WHO recognized the need for research on stigma because of its significant relationship with transmission and control. The most recent descrip-tion of stigma and the process of stigmatization in leprosy has been published by Bainson and van den Borne (17). This and other work draws attention to the extent and limitations of current knowledge. Bainson and van den Borne compare the physical and social course of the disease, describing the char-acteristics of leprosy that contribute to stigmatiza-tion and the responses they evoke. They identify five cognitive dimensions of disease that contrib-ute to stigma:

1. Concealability – the ease with which signs of the disease may be hidden.

2. The course of the disease, whether it is progres-sive, chronic or incurable.

3. The disease’s aesthetic impact or perceived ugliness.

4. The origin, specifically whether responsibility may be attributed to the person affected.

5. The peril dimension, relating to the risk of infection or uncleanness.

They go on to describe how the adverse reactions of the community are expressed in fear, insensitivi-ty and withdrawal, and devalue in the status of the person affected by leprosy. Eventually the affect-ed person loses social status and becomes progres-

sively isolated from society, family and friends. In the worst case, loss of the ability to work and social ostracism lead to dehabilitation, begging and hos-tility towards society. This reflects the situation described by Goffman (18), where stigmatized and stigmatizer each see the other as a threat.

The suggestion from the literature is that the impact of stigma is not only related to visible impairments. Scambler (19) asserts that where perceived stigma results in successful concealment, the disruption to peoples’ lives may be greater than that of enacted stigma. Rather than a simple relationship between disability and stigma, this suggests a complex rela-tionship in which community attitudes may have an impact on everyone affected by leprosy, not just those individuals with visible signs of disability.

While there are reports suggesting that stigma is reducing, there is little evidence of a complete understanding of the processes of stigmatization. Bainson and Van den Borne call for more informa-tion about the relative importance of the cognitive dimensions in engendering stigma. They pose ques-tions about how the characteristics of the individual and their symptoms influence the degree of stigma – the significance of age, sex, personality, and status or role within the community. There is the sugges-tion that integrated programmes may be more effec-tive in reducing stigma than those treating leprosy as a separate disease. This is reinforced by the recent work reported by Arole (20).

Stigma is known to contribute to the stress of any ill-ness experience and may be a barrier to help-seek-ing behaviour due to personal shame or fears of the negative attitudes of health workers. Morrison (21), who is primarily concerned with the impact of lep-rosy on women, affirms that this applies in leprosy. Bainson and Van den Borne recognize that stigma affects all aspects of leprosy control and is a threat to achieving the goal of elimination.

A workshop on stigma and the psychological conse-quences was held during the International Leprosy Congress in Brazil, August 2002. At this workshop, issues considered included defining the problem, the nature of stigma, the process and consequenc-es of stigmatization, and recent research. A report of the workshop and the recommendations for research will be published shortly.

Current research includes the development of a Participation Scale to assess the extent of partici-pation restrictions experienced by people affect-ed by leprosy. Related qualitative research seeks to develop screening tools to identify people at risk of


participation restrictions and people experiencing restrictions.

Questions:

1. Are the five cognitive dimensions identified by Bainson and van den Borne correct? Do IEC activities address each of these adequately?

2. Are leprosy service providers sufficiently aware of the potential for self-stigmatization? How can self-stigmatization be addressed?

SOCIOECONOMIC ASPECTS OF REHABILITATION

The challenge facing organizations seeking to reha-bilitate people affected by leprosy is to find a bal-anced approach which is caring yet encourages people to manage their own lives in the wider com-munity. The attitudes of family and community present a further challenge in formulating an appro-priate response. Arole (22) identified three key prin-ciples for rehabilitation work in leprosy:

1. A recognition of the broad impact of leprosy on the individual – physical, psychological, social and economic.

2. Responsiveness to the concerns of individu-als affected by leprosy, resulting in an approach that ensures their participation and restores dignity, thereby promoting empowerment and self-respect.

3. Responsiveness and involvement of the families and communities affected by leprosy. Members of the family and the community have an important role to play in rehabilitation.

While local issues and priorities are important, the Arole principles need to be reflected in objectives to restore dignity, reduce stigma, promote social inte-gration and improve economic status. Projects will work for greater community involvement and give more attention to groups with special needs, specifi-cally children, older people and women.

The preferred approach (23) to rehabilitation is participatory, with those directly affected playing a central role. Unless people participate and own the process, they will not be fully committed to it. This extends to people directly affected, their fami-ly members, community members, and associations of people affected by leprosy. Programmes must be holistic, aiming to improve physical, social and psychological functioning. Holistic programmes require teamwork by professional staff from a vari-ety of backgrounds and participation by those

affected, their families and communities. Effective rehabilitation requires communication and coopera-tion between all those providing care. The principle of sustainability requires that activities bring lasting benefit. The principle of integration requires an end to providing independent leprosy rehabilitation ser-vices, and the full integration of such services with-in the compass of community based rehabilitation (CBR). Gender sensitivity and sensitivity to special needs, for example the needs of children, are also a priority. Such programmes encompass an advoca-cy role. They bring further implications for organi-zational structure, communication, leadership and decision-making. Guidelines for socioeconomic rehabilitation have recently been published (24) and widely disseminated in a number of languages.

Research priorities focus largely on the need to define best practice. To what extent have current programmes adopted this approach? What are the organizational success factors? What specific dif-ficulties are encountered in this approach? There are broader questions too. What is the extent of the rehabilitation problem? How closely is it associat-ed with disability? What are the specific rehabilita-tion needs? Are existing CBR programmes ready to extend their services to people affected by leprosy?

CONCLUSIONS

Social behavioural aspects have been under-researched. An increasing volume of work is now being undertaken on socioeconomic rehabilitation. Application of behavioural sciences has much to contribute to leprosy control through work on the effectiveness of models of IEC, symptom recognition and help seeking behaviours, and adherence with treatment. Earlier case detection and more com-plete treatment will lead to better leprosy control. Quantitative methods can only take us so far; qual-itative approaches need to be used to make signifi-cant improvements to the quality of leprosy control.

References

1. Special issue on social aspects of leprosy. Leprosy Review, 2000, 71(4):417-516.

2. Williams PG et al. Social marketing to eliminate lepro-sy in Sri Lanka. Social Marketing Quarterly, 1998, 4(4):27-31.

3. Nicholls PG. Delayed presentation in leprosy – how to identify the causes: A guide to fieldwork. ILEP Co-ordinat-ing Bureau, 2002.


Lepr

osy

4. Bharath S et al. Correlates of psychiatric morbidity in patients with leprsosy. Indian Journal of Leprosy, 2001, 73(3):217-288.

5. Scott J. The psychosocial needs of leprosy patients. Leprosy Review, 2000, 71(4):486-91.

6. De Oliveira M. Emotional reactions of hansenia-sis patients with physical deformities. Hansenologia Internationalis, 1990, 15:16-23.

7. Angel R, Thoits P. The impact of culture on the cogni-tive structure of illness. Culture, Medicine and Psychiatry, 1987, 11:465-494.

8. Neylan TC et al. Illness beliefs of leprosy patients: use of medical anthropology in clinical practice. International Journal of Leprosy & Other Mycobacterial Diseases, 1988, 56(2):231-237.

9. van de Weg N et al. Explanatory models and help-seeking behaviour of leprosy patients in Adamawa State, Nigeria. Leprosy Review, 1998, 69(4):382-9.

10. Opala J, Boillot F. Leprosy among the Limba: illness and healing in the context of world view. Social Science & Medicine, 1996, 42(1):3-19.

11. Mull JD et al. Culture and ‘compliance’ among lepro-sy patients in Pakistan. Social Science & Medicine, 1989, 29(7):799-811.

12. Fassin D. Influence of social perceptions of leprosy and leprosy patients on public health programs. International Journal of Leprosy & Other Mycobacterial Diseases, 1990, 58(1):111-114.

13. Elissen MC. Beliefs of leprosy patients about their ill-ness. A study in the province of South Sulawesi, Indonesia. Tropical & Geographical Medicine, 1991, 43(4):379-382.

14. Becx-Bleumink M. Priorities for the future and pros-pects for leprosy control. International Journal of Leprosy & Other Mycobacterial Diseases, 1993, 61(1):82-101.

15. Anandaraj H. Psychosocial dimensions of drug default in leprosy. Indian Journal of Leprosy, 1986, 58(3):424-430.

16. Heynders ML, Meijs JJ, Anderson AM. Towards an understanding of non-compliance. An assessment of risk factors for defaulting from leprosy treatment. Leprosy Review, 2000, 71(3):369-376.

17. Bainson KA, Van den Borne B. Dimensions and proc-ess of stigmatization in leprosy. Leprosy Review, 1998, 69(4):341-350.

18. Goffman E. Stigma. Notes on the management of spoiled identity. London, Penguin Group, 1963.

19. Scambler G. Stigma and Disease: changing paradigms. The Lancet, 1998, 352(9):1054-1055.

20. Arole S et al. Social stigma: a comparative qualitative study of integrated and vertical care approaches in leprosy. Leprosy Review, 2002, 73(2):186-196.

21. Morrison A. A woman with leprosy is in double jeop-ardy. Leprosy Review, 2000, 71(2):128-143

22. Arole RS. Report on ILA Congress, Beijing, 1998. International Journal of Leprosy and Other Mycobacterial Diseases, 1998, (4):532-599.

23. Nicholls PG, Smith WCS. Developments and trends in rehabilitation in leprosy. Selected Readings in CBR, Series 2, CBR in Transition. Asia Pacific Disability Rehabilitation Journal, 2001.

24. Nicholls PG. Guidelines for Social and Economic Rehabilitation. Leprosy Review, 2000, 71(4):422-465.


Lepr

osy

Annex 4 WORKING PAPER: Chemotherapy and chemoprophylaxis of leprosy


CHEMOTHERAPY AND CHEMOPROPHYLAXIS OF LEPROSY

Baohong JiBactériologie et Hygiène, Faculté de Médecine Pitié-Salpêtrière, Paris, France

CHEMOTHERAPY

Newer generation MDT regimens

After 2005, which is the new target date for global elimination of leprosy, the disease will still exist and new patients will continue to emerge, but control programmes may be significantly weaker. Under this very complicated situation, newer chemother-apeutic regimens that are more effective and opera-tionally less demanding are required (1). To develop newer generation MDT regimens, powerful bacteri-cidal drugs against M. leprae are needed. Previous experience (2) demonstrated that screening of exist-ing compounds is the only cost-effective way to develop drugs for leprosy, and should be encour-aged. The most productive approach is to screen compounds that display powerful activity against either a wide spectrum of gram-positive microor-ganisms in general or cultivable mycobacterium in particular, or that exhibit pharmacokinetic proper-ties more favourable than those exhibited by the member of the class presently employed for treat-ment of leprosy (3).

The discovery of a series of new drugs (2) with promising bactericidal activity against M. leprae has made possible the formulation of newer MDT reg-imens. A highly desirable new regimen is one that would permit all of the components to be adminis-tered once monthly under supervision, which would significantly reduce the risk of emergence of rifam-picin resistance caused by irregular administration of the daily dapsone-clofazimine component, and would also simplify the treatment. The combina-tion of rifampicin-ofloxacin-minocycline (ROM) is the first fully supervisable, monthly administered regimen (4), and the efficacy of multiple monthly doses for treatment of MB and PB leprosy has been tested in field trials in three different countries (5). Recent findings from mouse experiments indicate that rifapentine and moxifloxacin are significant-ly more bactericidal, respectively, than rifampicin and ofloxacin, and that the combination rifapentine-moxifloxacin-minocycline (PMM) is far more bacte-ricidal than the ROM combination (3). The efficacy

of PMM is currently being compared with that of ROM in a short-term clinical trial among leproma-tous leprosy patients.

After the success of single-dose ROM for the treat-ment of single-lesion PB leprosy (6,7), the possibility of treating multiple-lesion PB leprosy with single-dose ROM is being tested in India (8). To accumu-late more reliable information, additional trials are needed and post-treatment follow-up should be lon-ger. If the results of the trials demonstrate that sin-gle-dose ROM or PMM display therapeutic results in all PB leprosy similar to those of the standard MDT regimen, this will revolutionize chemotherapy for PB leprosy and save significant resources which can be used in other important activities.

A common regimen for PB and MB leprosy

A common regimen for the treatment of both PB and MB leprosy is desirable. However, because the size of the bacterial populations and the underlying immunological responses are so different between PB and MB leprosy, the requirements for chemother-apy, especially the number of drugs and duration of treatment, are bound to be very different; a common regimen would appear likely to result in over-treat-ment of PB leprosy or under-treatment of MB lep-rosy. Recently, the WHO Technical Advisory Group (TAG) on Elimination of Leprosy proposed “imple-mentation of a uniform six-months MB/MDT regimen for all patients” (9). This caused severe crit-icism from many leprosy workers because there is no information on the five-year relapse rate, which is a key parameter in assessing the long-term effica-cy of MDT among MB patients who have received 12-months of MDT. Thus there is no justification to test the possibility of further shortening the duration of MDT for MB leprosy to six months. Currently, a research protocol on a uniform MDT (U-MDT) regi-men for all types of leprosy (10) is being widely cir-culated. The project will involved 2500 MB and 2500 PB patients, who will be examined, clinically only, for evidence of relapse up to five years after comple-tion of treatment. The major weaknesses of the pro-tocol are that:

• Because several million PB cases have already been treated successfully with six-month two-drug MDT, it is not necessary to include PB patients in the trial (half the resources could be saved by not including PB patients).

• The definition of MB leprosy (10) is too broad and includes many cases who are in fact PB leprosy from the bacteriological and chemother-apeutic points of view (11).

• The definition of relapse (10) is too vague and it


will be difficult to distinguish relapse from lep-rosy reactions. More important is that, because skin-smear examination, one of the key indica-tors for diagnosing MB relapse (12,13), is not employed, the quality of diagnosing MB relapse will be compromised.

• Because the average incubation period of MB relapse after treatment with rifampicin-con-taining regimens is at least five years, patients should be followed up for more than five years after stopping treatment, otherwise only part of the relapse cases will be detected.

The magnitude of MB relapse after MDT is not yet ascertained, and the possible existence of a high-er risk subgroup of MB leprosy patients cannot be ruled out. The MB relapse rate has been reported to be very low, about 0.1%, among patients treated with MDT for 24 months or longer in routine pro-grammes (7). Because of the very low relapse rate, post-MDT surveillance (11) was discontinued at the same time as the duration of MDT for MB leprosy was progressively shortened. However, results from the Institut Marchoux (13) in Bamako (Mali) and the Central JALMA Institute (14) in Agra (India), dem-onstrate the existence of a subgroup of MB patients with a strong tendency to relapse after 24 months of MDT, as high as 4-7 per 100 patient-years among patients with an initial bacterial index (BI) (i.e. the average BI of 4 to 6 sites before MDT) of ≥ 4.0, far higher than among patients with an initial BI < 4.0, suggesting that high initial BI is the most impor-tant risk factor for MB relapse. In addition, relaps-es occurred late, on average at least 5 ±2 years after stopping treatment (12,13). Because there is no easy explanation for the deep disagreements regarding the magnitude of MB relapse after 24-month MDT, and because of the possible existence of a higher risk subgroup of MB patients who are prone to relapse, it is necessary to collect more information from long-term follow-up of MB patients after completion of MDT.

Since 1998, the great majority of MB patients have been treated with MDT for only 12 months (15-17). However, there is no information about the five-year relapse rate. Apparently, determination of the relapse rate after 12-month MDT is highly rele-vant, and should be considered as a top priority for research.

Drug resistance

Emergence of rifampicin resistance would create tremendous difficulty for the treatment of individu-al patients, and its widespread dissemination would pose a serious threat to achieving the final goal

of leprosy control. Previous experience (18) indi-cates that rifampicin resistance could emerge rath-er rapidly in a non-negligible proportion of patients whose treatment regimens were inappropriate. Although more than 10 million leprosy patients in the world have completed treatment with MDT, and rifampicin-resistant leprosy has not been reported among these patients (7,17), one must be cautious in interpreting the findings, because:

• post-MDT surveillance for relapse has been dis-continued

• during the last decade, rifampicin-susceptibil-ity testing has rarely been carried out, and the results are not always dependable.

Therefore, the current situation regarding rifampi-cin-resistant leprosy in unclear. Before the problem becomes so frequent that it threatens leprosy con-trol, solid information about its magnitude should be collected from different part of the world. Due to administrative, financial and technical rea-sons, it is no longer feasible to undertake a relative-ly large-scale survey of rifampicin-resistant leprosy by mouse footpad technique. On the other hand, because the available results of polymerase chain reaction (PCR)-based DNA sequence analysis of the rpoB gene of M. leprae were in full concordance with those of the susceptibility testing carried out in the mouse footpad system (19-22), the method could be applied as a cost-effective alternative tech-nique for monitoring rifampicin-resistant leprosy. Although more studies on the association between rifampicin resistance and rpoB mutation, particular-ly at positions other than Ser531 or His526, should be pursued, it is reasonable to conclude that, based on identification of rpoB mutation with amino acid substitution of Ser531 or His526, this approach may lead to the diagnosis of a good 80% of rifampicin-resistant strains of M. leprae (22,23).

Regarding a survey of rifampicin-resistant leprosy, as a first step, this should focus on acquired or sec-ondary rifampicin resistance, which probably exists mostly among MB patients who have relapsed after completion of MDT. Therefore a certain proportion of MB patients should be systematically examined both clinically and bacteriologically after comple-tion of MDT (23). Such a survey may encounter significant difficulties, especially operational diffi-culties in the field, but it is probably the only way to define the magnitude of the threat to leprosy control presented by rifampicin resistance.

Recently there have been reports of multidrug-resis-tant M. leprae (22, 24-26). Besides resistance to rifam-picin, the strains were also resistant to at least one


more drug other than dapsone, including ofloxacin (22,25,26) and sparfloxacin (25). Although the num-ber of multidrug-resistant strains remains small, their occurrence is indeed an alarm bell and must be closely scrutinized.

Accompanied MDT

Adherence (or compliance) of patients is crucial to the success of treatment. Poor adherence to self-administration of treatment is a common behav-ioural problem among patients suffering from chronic diseases (27,28), including TB (29-31) and leprosy (32-34). It has been well documented that the treatment behaviour of most patients is unpredict-able (35). Among leprosy patients, the magnitude of poor adherence to dapsone self-administration became apparent only when the urinary dapsone/creatinine ratio method (36,37) for monitoring ingestion of dapsone was established and tested in many leprosy control centres. A review of the results of urine testing concluded that only about half of the prescribed dapsone was actually ingested (32). Furthermore, studies also revealed that mere atten-dance at the clinic or collection of drugs by lepro-sy patients was not a reliable indicator of regular drug self-administration (38), as had been observed among TB patients (29). With MDT, only 70% (38) to 80% (39) of patients were found to adhere to self-administration of the daily component of MDT regimens when the monthly component was admin-istered under supervision, suggesting that adher-ence to the self-administered component of MDT regimens remains poor.

Although a number of alternative means to improve adherence exist (40), supervised (or directly observed) administration is the only proven way to ensure that a patient receives treatment with the cor-rect drugs, in the correct dosage, at the correct inter-vals (41,42). Based on experience with supervised administration of TB treatment, one of the principles of the MDT regimens recommended by the WHO Study Group on Chemotherapy of Leprosy for Control Programmes was that the monthly compo-nent of the regimens – rifampicin alone for PB lepro-sy and rifampicin plus a supplementary larger dose of clofazimine for MB leprosy – should be admin-istered under the supervision of a health worker (11). By the time of the seventh meeting of the WHO Expert Committee on Leprosy in 1997, more than 8.4 million leprosy patients had completed treatment with MDT in which the monthly component was administered under supervision (7).

However, to accelerate the leprosy elimination pro-cess, recently the WHO leprosy programme and

its TAG have changed dramatically their position on supervised therapy. They concluded that, after the first dose of MDT, “supervision of the subse-quent monthly component of MDT regimens is no longer essential”(9). Further, based on this conclu-sion, they recommended large-scale implementa-tion of accompanied MDT (AMDT) (9), which refers to a policy that patients are provided the entire sup-ply of MDT drugs – six months of medication for a PB case and 12 months for a MB case – at the time of diagnosis, while choosing someone close to them to accompany them with their treatment (16,17). Some members of TAG even believe that monthly super-vision “hampers integration and is not user-friend-ly”, and that “providing patients with a full course of treatment on their first visit is both patient- and staff-friendly and will improve compliance” (9).

The recommendation to discontinue supervision of monthly drug administration appears to be a sim-ple solution to the difficult problem of implement-ing supervised therapy, but the solution is obviously wrong. Not only have WHO and its TAG confused the operational difficulties of implementing super-vised therapy with the technical justifications for discontinuing its application, and ignored com-pletely the fact of poor adherence of patients to self-administered medication, but, more importantly, the recommendation lacks evidence-based justification. Furthermore, the recommendation also neglects the importance of regular contact between health work-ers and leprosy patients, which facilitates early detection and management of various complica-tions, crucial for prevention of impairments.

Experience with AMDT has yet to be document-ed. It is unclear whether this approach has ever been tested in the field and the whole concept of the AMDT policy is extremely vague. For example, it is unclear:

• Whether AMDT is to be applied as a routine or only in special situations.

• Who may be chosen to supervise the patient’s treatment – health workers, community volun-teers, or family members of the patients? What is the order of preference? In TB, opinions dif-fer regarding supervision by family mem-bers, which is common in DOT programmes; most workers believe that supervision by fam-ily members is less reliable and even ineffec-tive (43-45), and some national TB programmes, such as that of India, have clearly defined the DOT supervisor as someone outside the family (45).

• How AMDT “helps” (17) a patient to complete a full course of treatment. Is the person who


accompanies expected to observe the patient swallow each monthly dose of treatment?

• How to train and supervise AMDT by health workers.

Although a number of essential questions about AMDT remain to be answered, AMDT has been rap-idly and intensively implemented in the field. In an increasing number of national programmes, the total quantity of MDT blister packs is provided at the time of diagnosis to all patients, including those patients living rather close to treatment centres, but the AMDT supervisor either does not exist or lacks training and supervision. Consequently, one can-not be certain that the MDT drugs are indeed self-administered by the patients. Can so reckless a policy be termed “patient- and staff-friendly”?

In conclusion, with large-scale implementation of AMDT, the quality of treatment is a matter of real concern. Without a guarantee of quality, quantita-tive achievement or a declaration of leprosy elimi-nation is meaningless. To avoid building the leprosy elimination monument on sand, we must not con-sider only the short term. Every effort should be made to maintain and improve the basic quality of diagnostics and treatment in the field; these tasks are as important as increasing the accessibility of MDT to the patients. Therefore, it is time to replace wishful thinking with evidence-based practice, and discontinue the implementation of AMDT as a rou-tine in the field.

Defaulter

A defaulter has been defined as a patient who has not collected MDT treatment for 12 consecutive months (15). This is a purely arbitrary decision. It has been recommended that defaulters who cannot be retrieved be removed from the register (15), and that the register should be updated at least annual-ly (15,16). Consequently, removing defaulters from the register has become one of the important mecha-nisms to reduce the leprosy prevalence rate. However, a significant proportion of so-called defaulters have not really disappeared from the community, so indiscriminately removing them from the register, as if they never existed, is not a reasonable solution. First of all, every effort should be made to prevent the absentee becoming a defaulter. A serious attempt should be made to trace absentees, beginning at the time of their first absence. Regarding those who have already become defaulters, depending on the reason for default, dif-ferent actions should be taken. Those who have died or permanently migrated from the country

should be removed from the register, whereas those who have moved out of the district or are taking treatment elsewhere should be transferred rather than removed from the register. For the remaining defaulters, whatever the reason for default, as long as they continue to live in the district and have yet to complete the full course of MDT treatment, by definition they are “cases” (15,16) and may contin-ue to be sources of transmission. Instead of being removed from the register, the programme should encourage the health workers, with the assistance of the local community, to actively retrieve all default-ers.

When the defaulter returns to the health centre, the current policy is that a new course of MDT will be given only to those who have active skin lesions, new nerve involvement, or signs of leprosy reac-tion (15). The justification of such policy is arguable because it is difficult for general health workers to deal with the criteria concerning signs of activity, particularly among MB patients close to the lepro-matous end of the spectrum. The policy also creates confusion with regard to the duration of MDT, as if it depends only upon the signs of activity. Because, by definition, a defaulter has not completed MDT treatment, it seems more reasonable that a new course of MDT should be given to every ex-default-er after retrieve or return.

CHEMOPROPHYLAXIS OF LEPROSY (46)

Recently, because the new case detection rate has not diminished following implementation of MDT, there has been renewed interest in preventive thera-py for leprosy.

Regimens for chemoprophylaxis in leprosy

The regimen should be highly effective for treatment of leprosy, relatively non-toxic, low cost, and prefer-ably orally administered. It is important to point out that the target population is healthy and asymptom-atic, sub-clinically infected, does not need or accept to be treated as leprosy patients, and may not toler-ate side effects of treatment which are normally tol-erated by leprosy patients.

Both dapsone (47-49) and acedapsone (51-53) have been found capable of providing significant, about 50%, protective effect against leprosy, but it is unclear whether sulfone may prevent the occur-rence of lepromatous, or skin-smear positive, MB leprosy. If today there is a need to apply chemopro-phylaxis in leprosy, sulfone is no longer appropriate because dapsone-resistant M. leprae has become a widespread phenomenon since the end of the 1970s


(11) and also, because the duration of treatment has to be long due to the weak bactericidal activity of dapsone, there would be tremendous operational difficulties, especially poor adherence.

In view of a number of facts and assumptions (46), two principles are proposed in developing newer generation prophylactic regimens: • the treatment should be administered in not

more than a single dose• the regimen should always contain rifampicin.

Two different regimens have recently been tested for chemoprophylaxis: a single dose of the combination rifampicin-ofloxacin-minocycline, or ROM (54), and a single dose of rifampicin, either 25 mg/kg body weight (55) or 10 mg/kg (56). Because a single dose of ROM appears to be no more bactericidal than a single dose of rifampicin alone (4), and furthermore, the small bacterial population in a subclinically infected subject does not require an accompanying drug to prevent selection of rifampicin-resistant mutants, the addition of ofloxacin and minocycline to rifampicin will unnecessarily increase the cost and risk of side effects. Therefore, it seems more rea-sonable to give a single dose of rifampicin alone for chemoprophylaxis.

In the only published trial of rifampicin chemopro-phylaxis, a single dose of rifampicin alone, at a dos-age of 25 mg/kg, was tested in Southern Marquesas Island (55). After ten years of follow-up, it was con-cluded that the protective effect was only 35-40% (55).

Up to now, more than ten million leprosy patients have been treated with MDT containing multiple monthly doses of 600 mg rifampicin, and have tol-erated the treatment well. Nevertheless, the effec-tiveness and tolerance of the two different dosages of rifampicin, i.e. of 1500 mg (approximately 25 mg/kg/dose) versus 600 mg (approximately 10 mg/kg/dose), have not been directly compared in the same clinical trial. Until there is clear evidence that a sin-gle 1500 mg dose of rifampicin is more bactericidal than, and as well tolerated as, a 600 mg dose, rifam-picin should be administered for chemoprophylaxis in a dose of 600 mg.

With respect to the potential risk for emergence of rifampicin resistance following chemoprophylax-is with a single dose of rifampicin, the small bac-terial population of a subclinically infected person is unlikely to include a single rifampicin-resistant mutant, and therefore the risk of rifampicin resis-tance is probably negligible. On the other hand, if, for whatever reason, the bacterial population size is

larger than expected, and even includes rifampicin-resistant mutants, the emergence of rifampicin resis-tance is still very unlikely because a single dose of rifampicin is insufficient to select resistant mutants, as has been shown by the relapse of MB patients after a single dose of rifampicin (12,18).

Limitations of chemoprophylaxis in leprosy

The epidemiological profile of leprosy indicates that, to prevent a single case of leprosy, hundreds or even thousands of subjects need to be treated (50). Whatever regimen is applied, if trying to cover an entire population with chemoprophylaxis, the direct and indirect costs will be prohibitively high with tremendous operational difficulties, where-as the yield will be rather limited (50,54,55), so che-moprophylaxis is unlikely to be applied as a routine method for leprosy control. If chemoprophylaxis is confined only to a high-risk sub-population, i.e. to household contacts of leprosy patients, the bene-fit will be only 15% (50) because the contribution of household contacts to the total number of new cases in a population is no more than 30% and the effica-cy of chemoprophylaxis under routine conditions is 50% (bear in mind that the maximum achieved effi-cacy of chemoprophylaxis has been no more than 75% in ideal conditions). Thus, from the leprosy control point of view, confining chemoprophylaxis to high-risk sub-populations represents only a very modest contribution. On the other hand, because chemoprophylaxis has shown significant protec-tive effect among high-risk individuals (47-50), it may offer individual benefits in situations of excep-tionally high risk. Nevertheless, the effect of chemo-prophylaxis will most likely be transitory and, after the effect has waned, the high-risk individual could immediately be re-infected with M. leprae as long as transmission persists. Therefore, the index case and all known leprosy patients in the local community must be covered by chemotherapy before chemo-prophylaxis is begun.

References

1. Report of the International Leprosy Association Technical Forum. International Journal of Leprosy and Other Mycobacterial Diseases, 2002, 70:S1-S62.

2. Ji B. Prospect for chemotherapy of leprosy. Indian Journal of Leprosy, 2000, 72:35-46.

3. Consigny S et al. Bactericidal activities of HMR 3647, moxifloxacin, and rifapentines against Mycobacterium lep-rae in mice. Antimicrobial Agents and Chemotherapy, 2000, 44:2919-2921.


4. Ji B et al. Bactericidal activity of a single-dose com-bination of ofloxacin plus minocycline, with or with-out rifampin, against Mycobacterium leprae in mice and in lepromatous patients. Antimicrobial Agents and Chemotherapy, 1998, 42:1115-1120.

5. Daumerie D. Current World Health Organization-spon-sored studies in the chemotherapy of leprosy. Leprosy Review, 2000, 71:88-90.

6. Single-lesion Multicentre Trial Group. Efficacy of sin-gle-dose multidrug therapy for treatment of single-lesion paucibacillary leprosy. Indian Journal of Leprosy, 1997, 69:121-129.

7. WHO Expert Committee on Leprosy. Seventh Report. Geneva, World Health Organization, 1998 (WHO Technical Report Series, no.874).

8. Gupte MD. Field trials of a single dose of the combina-tion rifampicin-ofloxacin-minocycline (ROM) for the treat-ment of paucibacillary leprosy. Leprosy Review, 2000, 71:S77-S80.

9. Report on the Third Meeting of the WHO Technical Advisory Group on Elimination of Leprosy. Geneva, World Health Organization, 2002 (document number WHO/CDS/CPE/CEE/2002.29).

10. Uniform MDT regimen for all leprosy patients. Protocol. Geneva, World Health Organization, 20 August 2002.

11. WHO Study Group. Chemotherapy of leprosy for con-trol programmes. Geneva, World Health Organization, 1982 (WHO Technical Report Series, no. 675).

12. Marchoux Chemotherapy Study Group. Relapse in multibacillary leprosy patients after stopping treatment with rifampin-containing combined regimens. International Journal of Leprosy, 1992, 60:525-535.

13. Jamet P, Ji B, Marchoux Chemotherapy Study Group. Relapse after long-term follow up of multibacillary patients treated with WHO multidrug regimen. International Journal of Leprosy, 1995, 63:195-201.

14. Girdhar BK, Girdhar A, Kumar A. Relapses in multi-bacillary leprosy patients: effect of length of therapy. Leprosy Review, 2000, 71:144-153.

15. A guide to eliminating leprosy as a public health prob-lem. Second edition. Geneva, World Health Organization, 1997 (document number WHO/LEP/97.1).

16. Guide to eliminate leprosy as a public health problem. First edition. Geneva, World Health Organization, 2000.

17. The final push strategy to eliminate leprosy as a pub-lic health problem. Questions and answers. First edition. Geneva, World Health Organization, 2002.

18. Grosset JH et al. Study of 39 documented relaps-es of multibacillary leprosy after treatment with rifampin. International Journal of Leprosy, 1989, 57:607-614.

19. Honoré N et al. A method for rapid detection of rifampiicin-resistant isolates of Mycobacterium leprae. Leprosy Review, 2001, 72:441-448.

20. Honoré N, Cole ST. Molecular basis of rifampin resist-ance in Mycobacterium leprae. Antimicrobial Agents and Chemotherapy, 1993, 37:414-418.

21. Honoré N et al. A simple and rapid technique for the detetion of rifampicin resistance in Mycobacterium leprae. International Journal of Leprosy, 1993, 61:600-604.

22. Cambau E et al. Molecular detection of rifampin and ofloxacin resistance for patients who experience relapse of multibacillary leprosy. Clinical Infectious Diseases, 2002, 34:39-45.

23. Ji B. Rifampicin resistant leprosy: A review and a research proposal of a pilot study. Leprosy Review, 2002, 73:2-8.

24. Shetty VP, Uplekar NW, Antia NH. Primary resistance to single and multiple drugs in leprosy – a mouse footpad study. Leprosy Review, 1996, 67:280-286.

25. Matsuoka M, Kashiwabara Y, Namisato M. A Mycobacterium leprae isolate resistant to dapsone, rifampin and sparfloxacin. International Journal of Leprosy, 2000, 68:452-455.

26. Maeda S et al. Multidrug resistant Mycobacterium lep-rae from patients with leprosy. Antimicrobial Agents and Chemotherapy, 2001, 45:3635-3639.

27. Sackett DL. Introduction. The magnitude of compli-ance and noncompliance. In: Sackett DL and Haynes RB eds. Compliance with therapeutic regimens. Baltimore and London, Johns Hopkins University Press, 1976.

28. Haynes RB, Tayor DW, Sackett DL, eds. Compliance in health care. Baltimore and London, Johns Hopkins University Press, 1979.

29. Fox W. Problem of self-administration of drugs, with particular reference to pulmonary tuberculosis. Tubercle, 1958, 39:269-274.

30. Fox W. Self administration of medicaments. A review of published work and a study of the problems. Bulletin of the International Union against Tuberculosis, 1961, 31:307-331.

31. Fox W. Ambulatory chemotherapy in a developing country: clinical and epidemiological studies. Advances in Tuberculosis Research, 1963, 12:28-149.

32. Ellard GA. Drug compliance in the treatment of lepro-sy. Leprosy Review, 1981, 52:201-213.


Lepr

osy

33. Huikeshoven H. Patient compliance with dapsone administration in leprosy. International Journal of Leprosy, 1981, 49:228-258.

34. Huikeshoven H. Patient compliance in leprosy control: a necessity in old and new regimens. International Journal of Leprosy, 1985, 53:474-480.

35. Sbarbaro JA. Public health aspects of tuberculosis: supervision of therapy. Clinics in Chest Medicine, 1980, 1:253-263.

36. Ellard GA et al. Urine tests to monitor the self-adminis-tration of dapsone by leprosy patients. American Journal of Tropical Medicine and Hygiene, 1974, 23:464-470.

37. Ellard GA, Gammon PT, Harris JM. The application of urine tests to monitor the regularity of dapsone self-admin-istration. Leprosy Review, 1974, 45:224-234.

38. Ellard GA et al. Clofazimine and dapsone compliance in leprosy. Leprosy Review, 1988, 59:205-213.

39. Becx-Bleumink M. Duration of multidrug thera-py in paucibacillary leprosy patients; experience in lep-rosy control programme of the All Africa Leprosy and Rehabilitation Training Centre (ALERT) in Ethiopia. International Journal of Leprosy, 1992, 60:436-444.

40. Sumartojo E. When tuberculosis treatment fails. A social behavioural account of patient adherence. The American Review of Respiratory Disease, 1993, 147:1311-1320.

41. Treatment of tuberculosis. Guidelines for nation-al programmes. Second edition. Geneva, World Health Organization, 1997 (document number WHO/TB/97.220).

42. Fox W, Ellard G, Mitchison DA. Studies on the treat-ment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units, 1946-1986, with rel-evant subsequent publications. International Journal of Tuberculosis and Lung Disease, 1999, 3:S231-279.

43. Frieden T, Sbarbaro JA. The slippery slope to slop-py DOTS. International Journal of Tuberculosis and Lung Disease, 2002, 6:371-372.

44. Mathema B et al. Tuberculosis treatment in Nepal: a rapid assessment of government centers using differ-ent types of patient supervision. International Journal of Tuberculosis and Lung Disease, 2001, 5:912-919.

45. Khatri GR, Frieden TR. Rapid DOTS expansion in India. Bulletin of the World Health Organization, 2002, 80:457-463.

46. Ji B, Grosset JH. Drugs and regimens for preventive therapy against tuberculosis, disseminated Mycobacterium avium complex infection and leprosy. International Journal of Leprosy, 1999, 67:S45-S55.

47. Noordeen SK. Chemoprophylaxis in leprosy. Leprosy in India, 1968, 40:115-119.

48. Noordeen SK. Long-term effects of chemoprophylax-is among contacts of lepromatous cases. Results of a 8 1/2 years follow-up. Leprosy in India, 1977, 49:504-509.

49. Noordeen SK. Chemoprophylaxis. Health Cooperation Papers, 1982, 1:173-182.

50. Noordeen SK. Prophylaxis – scope and limitations. Leprosy Review, 2000, 71:S16-S20.

51. Russell DA et al. Acedapsone (DADDS) treatment of leprosy patients in the Karimui of Papua-New Guinea: sta-tus at six years. American Journal of Tropical Medicine and Hygiene, 1975, 24:485-495.

52. Russell DA et al. Experience with acedapsone (DADDS) in the therapeutic trial in New Guinea and the chemoprophylactic trial in Micronesia. International Journal of Leprosy, 1976, 44:170-176.

53. Russell DA et al. Acedapsone in the prevention of leprosy; field trial in three high prevalence villages in Micronesia. American Journal of Tropical Medicine and Hygiene, 1979, 28:559-563.

54. Diletto C, Blanc L. Leprosy chemoprophylaxis in Micronesia. Leprosy Review, 2000, 71:S21-S25..

55. Nguyr, LN, Cartel JL, Grosset JH. Chemoprophylaxis of leprosy in the Southern Marquesas with a single 25 mg/kg dose of rifampicin. Results after 10 years. Leprosy Review, 2000, 71:S33-S36.

56. Vijayakumaran P et al. Chemoprophylaxis against lep-rosy: expectations and methodology of a trial. Leprosy Review, 2000, 71:S37-S41.


Lepr

osy

Annex 5 WORKING PAPER: Leprosy – new opportunities in basic science


LEPROSY – NEW OPPORTUNITIES IN BASIC SCIENCE

Douglas B Young Centre for Molecular Microbiology and Infection, Imperial College, London SW7 2AZ, United Kingdom

The decade between initiation of the Mycobacterium leprae genome project and its final publication (1) witnessed a progressive decline in interest in lep-rosy research. This was caused by the perception that multidrug therapy provided a sufficient solu-tion to the clinical problems of leprosy, the fact that Mycobacterium tuberculosis presented a more tracta-ble experimental system than M. leprae for exploi-tation of the emerging techniques of mycobacterial genetics (2), and disappointing results with the heat-killed M. leprae vaccine developed under the IMMLEP programme (3). To take advantage of new opportunities arising from the genome sequence, there is a need to rebuild momentum in the lepro-sy research community. This can be achieved within a framework that combines research on the funda-mental biology of leprosy alongside research that addresses practical aspects of leprosy control.

FUNDAMENTAL BIOLOGY OF LEPROSY

Study of the genetic make-up of M. leprae is an important component of the general investigation of evolution of human pathogens and is of particu-lar relevance in the context of comparison with the closely related M. tuberculosis. Investigation of the dramatic neurological and immunological patholo-gies of leprosy provides a unique perspective that may increase understanding of normal human physiology.

Evolution of microbial genomes

The explosion of information from microbial genome sequencing projects has had a major impact in the field of evolutionary biology (4). There is an active interest in trying to understand how genetic exchange and genome reorganization have contrib-uted to the evolution of different pathogenic strat-egies (5). M. leprae provides an interesting example as an evolutionary snapshot of a genome in transi-tion (1). By comparison with M. tuberculosis, a quar-ter of the genome has already been deleted, and the large number of pseudogenes are thought to repre-sent intermediates on the way to gene loss. M. leprae has undergone a process of adenine thymine enrich-

ment that has been observed in several obligate pathogens (6). This may reflect loss of DNA repair enzymes that are required for correction of sponta-neous cytosine to uracil deamination.

To pursue research in this area, there is a need to col-lect information about genetic variation amongst M. leprae isolates; experience with M. tuberculosis indi-cates that deletions and single nucleotide polymor-phisms are likely to be particularly informative as evolutionary markers (7). Strategies to approach this would include detailed analysis of chromosomal DNA from one or more additional isolates prepared by armadillo passage. Partial coverage by shotgun sequencing would be sufficient to identify candi-date polymorphisms. This could be complemented by PCR-based analysis of target loci in clinical sam-ples to determine the extent of strain diversity at a population level. In addition to fundamental infor-mation about pathogenic mechanisms, investigation of M. leprae in an evolutionary context may provide some indication of when it adapted to human patho-genesis (8), and may allow us to determine wheth-er it is now on an inevitable pathway to extinction. An interesting aspect of such studies involves exam-ination of M. leprae DNA preserved in archaeolog-ical samples (9). This allows analysis of long-term changes in population structure, and could address the question of whether present day isolates of M. leprae differ from those that were prevalent in medi-eval Europe.

Host-pathogen interactions

Cellular microbiology – combining the tools of cell biology and microbiology – is at the forefront of current efforts to explore the host-pathogen inter-actions (10). In addition to its direct application to understanding pathogenesis, this field has generat-ed useful insights into the fundamental biology of signal transduction and cytoskeletal organization in mammalian cells. The neural predilection of M. lep-rae offers an opportunity for a novel perspective on the organization and physiology of human periph-eral nerves, and this has been exploited in a recent series of papers implicating phenolic glycolipid in neurotropism (11). There is considerable scope to extend these studies to investigate intracellular com-partmentalization of M. leprae in Schwann cells and other cell types. It would be interesting to determine why M. leprae is found in multiple cell types during infection, for example, in contrast to the apparently restricted cell tropism of M. tuberculosis.

A central component of research on host-pathogen interactions involves analysis of changes in patho-gen gene expression associated with adaptation to


an appropriate in vivo phenotype. The technical problems associated with direct analysis of in vivo phenotypes have been a central feature of lepro-sy research. Experience in isolating M. leprae from infected tissues and analysis of protein and lipid profiles may provide a useful model for parallel studies with other bacterial pathogens. Reciprocally, increased interest in the application of molecular approaches to histopathology may provide ways of examining leprosy lesions. Microarray-based whole genome expression profiling can be applied to char-acterization of the M. leprae transcriptome. This will depend on development of techniques for amplifi-cation of mycobacterial mRNA (12).

Immunology

There is considerable current interest in analysis of initial recognition of pathogens by innate immune mechanisms, and translation into signals that alert and direct the adaptive response. This is mediated in part by the family of toll-like receptors on macro-phages and dendritic cells, and includes release of a series of proinflammatory cytokines (13). M. leprae can accumulate in tissues to much higher levels than M. tuberculosis, and appears to present a less potent proinflammatory stimulus. Comparison of respons-es to the two pathogens, together with knowledge of surface components, may be useful in identi-fying molecular determinants regulating innate immune recognition. Understanding of inflammato-ry responses to M. leprae is of particular importance in the context of leprosy reactions.

The specific absence of a Th1 response to M. lep-rae antigens in lepromatous leprosy represents a remarkable model for studying immune regula-tion. Evidence from analysis of leprosy lesions sug-gests that this may in part reflect polarization of the immune response towards a Th2 phenotype (14), but other mechanisms of tolerance remain to be investigated. It is not clear whether Th1 aner-gy is a predisposing factor for lepromatous disease, or is a subsequent consequence of prolonged expo-sure to antigen. There is a current renewal of inter-est amongst basic immunologists in understanding mechanisms of peripheral tolerance and the role of regulatory T cell subsets (15); lepromatous leprosy would seem to provide an interesting challenge in this context. Findings from leprosy can be expected to generate insights into the less polarized immune changes underlying reactivation tuberculosis. While the immune response in infected humans should be the main target for research, experiments in geneti-cally manipulated mouse strains may assist in dis-secting fundamental aspects of immunity to M. leprae (16).

Host genetics

Twin studies demonstrate that there is an important genetic element in susceptibility to mycobacterial disease (17). Considerable effort has been invested in searching for genetic determinants of susceptibil-ity to tuberculosis in humans and in animal mod-els. Few clearcut results have been obtained; it is likely that multiple loci contribute to susceptibility. For leprosy, the presence of well-established clini-cal phenotypes may offer an advantage in facilitat-ing selection of tightly defined cohorts for genetic screens (18,19).

SUPPORTING LEPROSY CONTROL

In spite of the success of multidrug therapy over the last decade, there has been no obvious decline in the number of new cases of leprosy reported from high incidence countries (20). This raises the question as to whether passive case finding and treatment is suf-ficient to interrupt leprosy transmission, or whether additional intervention tools are required. The M. leprae genome offers a range of research opportuni-ties of direct relevance to current control strategies.

Drugs and drug resistance

The emergence of multidrug resistant organ-isms has had a major impact on tuberculosis con-trol. Although dapsone resistance was widespread in the pre-MDT era, rifampicin resistance has not yet presented a major problem for leprosy control. Molecular genetic tests for mutations associated with rifampicin resistance provide a convenient sur-veillance tool to monitor this situation (21). From a similar perspective, it would be of interest to iden-tify the genetic basis of M. leprae resistance to other drugs.

While it is unlikely that novel drugs will be devel-oped specifically for treatment of leprosy, it is important to have the ability to test whether newly developed antibiotics have any potential applica-tion in improved leprosy treatment. Assays based on measurement of transcriptional activity, and perhaps the use of reporter phage constructs (22), provide possible avenues for exploitation of genet-ic tools in development of novel tests to assess the effects of drugs on M. leprae.

Transmission

Monitoring transmission of M. leprae may provide a powerful tool for assessment of the impact of lep-rosy control strategies, since reduced transmis-sion may precede a reduction in disease incidence by years or even decades. In principle, transmis-


sion patterns can be analysed by studying immune responses in infected individuals, or by analysing the population structure of the pathogen.

Mycobacterial infection can be detected by anti-gen-specific immune responses manifest by delayed type hypersensitivity, T cell proliferation, or cyto-kine release. Antibody production represents an alternative readout, though this is likely to require presence of a higher concentration of antigen and may therefore be less sensitive. The most convenient current technologies involve measurement of inter-feron-� production by exposure of peripheral blood T cells to synthetic peptide antigens. The readout involves detection of soluble cytokine by enzyme linked immunosorbent assay (ELISA), or enumera-tion of cytokine-producing T cells by ELISpot. In the tuberculosis field, considerable enthusiasm has been generated by an ELISpot assay based on the ESAT6 antigen (23). Comparative genomics offers a pow-erful solution to the prolonged search for M. lep-rae-specific antigens for use in such an assay. Simple bioinformatic tools can be used to screen the limit-ed panel of M. leprae-specific open reading frames to identify peptides that include appropriate major histocompatibility complex binding motifs and lack cross-reactive homologues (24). Development of a specific test for M. leprae infection represents a very feasible short-term goal.

Molecular epidemiology has taken on an important role in tuberculosis research, with the use of strain typing to confirm reactivation disease (25), to distin-guish reinfection from relapse (26), and to estimate the prevalence of disease due to recent transmis-sion (27). When disease arises predominantly as a consequence of recent transmission, the result-ing isolates tend to share the same genetic features. When disease results from reactivation of some ear-lier infection, isolates are more likely to be genet-ically diverse. It is anticipated that the molecular epidemiology of leprosy will follow a similar pat-tern and that strain typing would therefore help clarify the relative importance of recent transmis-sion within an endemic community. Several poly-morphisms have been described for strain typing of M. leprae (28-30). The number of copies of a non-cod-ing triplet repeat sequence shows considerable vari-ation between clinical isolates (30). A diverse range of triplet repeat patterns was found in a panel of iso-lates obtained from the same single leprosy clinic at Hyderabad in India (SK Young, GM Taylor, unpub-lished), suggesting that this polymorphism may be useful for localized epidemiological mapping. Tools for the molecular epidemiology of leprosy will be generated by the fundamental research on evolu-tionary biology of M. leprae described above, and

will open up exciting new opportunities for practi-cal application.

Nerve damage

The need for new tools to assist in prevention of nerve damage during leprosy treatment has con-sistently been viewed as a high priority in lepro-sy research. Basic research on neurotropism and on immunology clearly have potential relevance in this area, which is discussed in detail in an accompany-ing working paper.

Vaccines

The search for an effective prophylactic vaccine pro-vided a central theme for TDR-sponsored leprosy research in the 1980s. An important finding from the resulting clinical trials was that BCG consistently confers protection against leprosy, and that this pro-tection is boosted by a second BCG vaccination (31). Both of these findings appear to be in contrast to experiences with the use of BCG against tuberculo-sis, and the repeat BCG result tends to contradict the prevailing thought that BCG is ineffective in indi-viduals with pre-existing mycobacterial immunity (32-33). A second mycobacterium, the ICRC bacillus, was also shown to elicit a protective effect, in this case after delivery as a killed vaccine (3). In terms of leprosy control, it would seem attractive to include repeat BCG (or an alternative vaccine) as part of any targeted strategy to reduce leprosy in high incidence areas. From a research perspective, it would be interesting to try and understand the nature of the immune response that is boosted by repeat BCG and that confers protection against M. leprae.

SUMMARY

Leprosy offers an interlinked series of research top-ics ranging from fundamental biology to practical application. To exploit these opportunities, there is a need to bring about some restoration of the extent and momentum of the leprosy research community. TDR can play a role in this by publicizing research opportunities, coordinating meetings of basic and applied scientists working on leprosy and related topics, and supplying seed money to encourage new investigators to take an interest in leprosy.

References

1. Cole ST et al. Massive gene decay in the leprosy bacil-lus. Nature, 2001, 409:1007-1011.

2. Glickman MS, Jacobs WR Jr. Microbial pathogenesis of Mycobacterium tuberculosis: dawn of a discipline. Cell, 2001, 104:477-85.


3. Gupte MD et al. Comparative leprosy vaccine trial in south India. Indian Journal of Leprosy, 1998, 70:369-88.

4. Doolittle RF. Microbial genomes multiply. Nature, 2002, 416:697-700.

5. Mira A, Klasson L, Andersson SGE. Microbial genome evolution: sources of variability. Current Opinion in Microbiology, 2002, 5:506-12.

6. Moran NA. Microbial minimalism: genome reduction in bacterial pathogens. Cell, 2002, 108:583-6.

7. Brosch R, et al. A new evolutionary scenario for the Mycobacterium tuberculosis complex. Proceedings of the National Academy of Sciences of the United States of America, 2002, 99:3684-9.

8. Sreevatsan S et al. Restricted structural gene polymor-phism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination. Proceedings of the National Academy of Sciences of the United States of America, 1997, 94:9869-74.

9. Taylor GM et al. A mediaeval case of lepromatous lep-rosy from 13-14th century Orkney, Scotland. Journal of Archaeological Science, 2000, 27:1133-8.

10. Falkow S. Cellular Microbiology is launched. Cellular Microbiology, 1999, 1:3-6.

11. Rambukkana, A. Molecular basis for the peripher-al nerve predilection of Mycobacterium leprae. Current Opinion in Microbiology, 2001, 4:21-7.

12. Talaat AM, Hunter P, Johnston SA. Genome-direct-ed primers for selective labeling of bacterial transcripts for DNA microarray analysis. Nature Biotechnology, 2000, 18:679-82.

13. Sieling PA, Modlin RL. Toll-like receptors: mammalian “taste receptors” for a smorgasbord of microbial invaders. Current Opinion in Microbiology, 2001, 5:70-5.

14. Yamamura MK et al. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science, 1991, 254:277-9.

15. Taams LS et al. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells. European Journal of Immunology, 2002, 32:1621-30.

16. Adams LB et al. The study of Mycobacterium leprae infection in interferon-gamma gene-disrupted mice as a model to explore the immunopathologic spectrum of lepro-sy. Journal of Infectious Diseases, 2002, 185 Suppl 1:S1-8.

17. Cook GS, Hill AVS. Genetics of susceptibility to human infectious disease. Nature Reviews. Genetics, 2001, 2:967-77.

18. Kang TJ, Chae GT. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunology and Medical Microbiology, 2001, 31:53-8.

19. Tosh K et al. A region of chromosome 20 is linked to leprosy susceptibility in a South Indian population. Journal of Infectious Diseases, 2002, 186:1190-3.

20. Lockwood DN. Leprosy elimination – a virtual phe-nomenon or a reality? British Medical Journal, 2002, 324:1516-8.

21. Honore N et al. A method for rapid detection of rifampicin-resistant isolates of Mycobacterium leprae. Leprosy Review, 2001, 72:441-8.

22. Jacobs WR et al. Rapid assessment of drug susceptibil-ities of Mycobacterium tuberculosis by means of luciferase reporter phages. Science, 1993, 260:819-22.

23. Lalvani A et al. Enhanced contact tracing and spatial tracking of Mycobacterium tuberculosis infection by enu-meration of antigen-specific T cells. Lancet, 2001, 357: 2017-21.

24. Dockrell HM et al. A postgenomic approach to identifi-cation of Mycobacterium leprae-specific peptides as T-cell reagents. Infection and Immunity, 2000, 68:5846-55.

25. Lillebaek T et al. Molecular evidence of endogenous reactivation of Mycobacterium tuberculosis after 33 years of latent infection. Journal of Infectious Diseases, 2001, 185:401-4.

26. van Rie A et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. New England Journal of Medicine, 1999, 341:1174-9.

27. Small PM et al. The epidemiology of tuberculosis in San Francisco. A population-based study using conven-tional and molecular methods. New England Journal of Medicine, 1994, 330:1703-9.

28. Fsihi H, Cole ST. The Mycobacterium leprae genome: systematic sequence analysis identifies key catabol-ic enzymes, ATP-dependent transport systems and a novel polA locus associated with genomic variability. Molecular Microbiology, 1995, 16:909-19.

29. Matsuoka M et al. Mycobacterium leprae typing by genomic diversity and global distribution of genotypes. International Journal of Leprosy and Other Mycobacterial Diseases, 2000, 68:121-8.

30. Shin YC et al. Variable numbers of TTC repeats in Mycobacterium leprae DNA from leprosy patients and use in strain differentiation. Journal of Clinical Microbiology, 2000, 38:4535-8.


Lepr

osy

31. Karonga Prevention Trial Group. Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of lep-rosy and tuberculosis in Malawi. Lancet, 1996, 348:17-24.

32. Brandt L et al. Failure of the Mycobacterium bovis BCG vaccine: some species of environmental mycobacte-ria block multiplication of BCG and induction of protective immunity to tuberculosis. Infection and Immunity, 2002, 70:672-8.

33. Black G F et al. BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies. Lancet, 2002, 359:1393–1401.


Lepr

osy

Annex 6 WORKING PAPER: The impact of multidrug therapy on trends in transmission


THE IMPACT OF MULTIDRUG THERAPY ON TRENDS IN TRANSMISSION

Abraham MeimaErasmus University Rotterdam, Department of Public Health Medical Decision Sciences, Rotterdam, The Netherlands.

LITERATURE REVIEW OF TRENDS IN LEPROSY NEW CASE DETECTION RATES

As a first step in investigating the impact of case detection and multidrug treatment (MDT) on lep-rosy, a literature review was conducted of trends in leprosy new case detection rates (NCDRs) as pub-lished in international literature (1). This review cov-ered nine countries and seven smaller geographical entities,a and NCDR data up to 1993. For the majori-ty of the areas/countries, NCDR trends were declin-ing (13 of 16 areas/countries had an average annual decline in NCDR of at least 2% per year). The liter-ature review may have suffered from publication bias, i.e. a tendency to publish papers on high qual-ity control programmes covering long periods of time or indicating successful leprosy control. In the review, an acceleration of declines in trends after the introduction of MDT was not visible. The long incu-bation period of leprosy could have masked such accelerations. For seven of the nine countries, addi-tional country data became available (2-7), which allowed for extension of the NCDR time series. A general impact of MDT on NCDR trends can still not be demonstrated.

NEW CASE DETECTION RATE TIME SERIES CONSTRUCTED ON THE BASIS OF COUNTRY DATA FOR 1985-2001

For 14 countries with at least 2000 newly detect-ed cases in 1998,b NCDR times series could be con-structed from the year 1985 onwards using country data obtained from subsequent issues of the Weekly Epidemiological Record (3-7) and from one confer-

ence report (2). The NCDR trends are highly vari-able, and underlying trends in leprosy transmission are unclear. Most probably, operational factors heav-ily influenced the NCDR trends: leprosy control activities were intensified following the 1991 World Health Assembly resolution to “eliminate leprosy as a public health problem by the year 2000”, and lep-rosy elimination campaigns were initiated. For 7 of 14 countries, NCDRs in the 1990s were either rath-er stable, or increased (Bangladesh, Brazil, Ethiopia, India, Indonesia, Mozambique, Sudan). For 3 of 14 countries, sudden sharp increases in NCDRs were observed in the late 1990s (Myanmar, Nepal, Madagascar). For 3 of 14 countries, a decreasing ten-dency – at least in more recent years – was observed (Philippines, China, Vietnam). For the remaining country (Guinea), strong fluctuations in the NCDR were observed.

REASONS FOR DECLINING TRENDS IN THE TRANSMISSION AND INCIDENCE OF LEPROSY

Declines in transmission and incidence (i.e. onset of disease) of leprosy may be related to several factors: – The period during which M. leprae is transmit-

ted, which can be reduced by early case detec-tion and chemotherapy treatment.

– BCG vaccination, which is widely administered as a preventive measure against tuberculosis but appears to afford more protection against leprosy than tuberculosis (8).

– Socioeconomic conditions, which are thought to play an important role in leprosy (9). Their improvement may result in a decline in inci-dence. Factors suggested to contribute are housing conditions, number of persons per household per room, family size and nutritional factors.

– Possible protection of tuberculosis against lep-rosy (10), either by immunization or by compet-ing risk.

FACTORS POSSIBLY LIMITING THE IMPACT OF BCG

In most developing countries, BCG is given in young childhood, and is only given once. Protective efficacies against leprosy ranged from 20% to 80% in randomized controlled trials (8). But the protec-tion was quite small in Asia where most patients are detected (two trials in India: 24% and 34% (11); one trial in Burma: 20%). It is also unclear whether the protection decreases with age. Thus, the impact of BCG on leprosy trends may be smaller than one would hope for. The impact also depends on

a Countries in the literature review: Philippines, Bhutan, Thailand, Malawi, Ethiopia, Rwanda, Brazil, Guyana, Mexico. Other areas: French Polynesia, Wenshan Prefecture (China), Weifang Prefecture (China), Visakhapatnam District (India), Shoa Region (Ethiopia), Uele Region (former Zaire), 3 Northern Provinces (Thailand). b The 14 countries are: Bangladesh, Brazil, China, Ethiopia, Guinea, India, Indonesia, Madagascar, Mozambique, Myanmar, Nepal, Philippines, Sudan, Vietnam.


the extent of coverage by BCG vaccination, which in many countries was not high before the 1990s (WHO disseminates country data regarding cover-age of immunization programmes through http://www.who.int/vaccines-surveillance/intro.html).

FACTORS POSSIBLY LIMITING THE IMPACT OF MDT BASED CONTROL

The assumption that case detection and treat-ment would reduce leprosy transmission is rea-sonable, but the reality may be more complicated. Individuals incubating the disease may already har-bour many bacilli, and it is possible that these indi-viduals already transmit M. leprae to others long before the onset of disease, given its long incubation period. Such transmission cannot be prevented by early detection and treatment.

A further problem is the delay between onset of disease and detection. For instance, in the ALERT control programme in Ethiopia, the average detec-tion delay exceeded two years. How easily lepro-sy is transmitted is not known. The group at risk of developing leprosy might be small, possibly due to genetic factors (leprosy infection is suggested to be much more common than leprosy disease [10,12]) or because close contact is important. Close contact – household and family, neighbours, social and busi-ness contact – has been suggested to play a key role in transmission (13). It is well possible that close contacts of a leprosy patient become infected rapid-ly. If close contact is indeed important, this may lead to a rapid decrease in the patient’s opportunities to transmit M. leprae. Thus, “early” detection may still be too late to prevent much of transmission by sub-sequent treatment. Other factors which could limit the impact of leprosy control have also been sug-gested, including carriage of M. leprae in the nose, persistence of M. leprae in the soil, and even animal reservoirs (14-17).

LEPROSY SIMULATION MODEL

An epidemiological model, SIMLEP, was developed in order to assess the impact of interventions on transmission. In this model, populations are divid-ed in mutually exclusive compartments, and a set of calculation rules is used to determine the number of transitions between the compartments in subse-quent time steps (18). Through this approach, trends over time can be simulated in transmission and onset of disease, case detection, numbers of incu-bating individuals, undetected leprosy patients, and patients on treatment.

ANALYSIS OF DISAPPEARANCE OF LEPROSY FROM NORWAY USING SIMLEP

Leprosy was still an endemic disease in Norway around 1850, but had virtually disappeared by 1920, long before effective anti-leprosy treatment became available. The downward trend is extreme-ly well documented (19). The decline coincided with continuous growth of the Norwegian economy. In Norway, a policy of isolation of patients was imple-mented. By legislation in 1877 and 1885, leprosy patients either had to be isolated in separate rooms in their houses, or had to be admitted to a hospital. The downward trend of new case detection in Norway was adequately reproduced with SIMLEP, and equally well for 8 (2 × 4) pairs of assumptions on contagiousness during the incubation period and on decrease of transmission opportunities (build-up of contagiousness during incubation period: yes/no; half-value time for transmission opportunities: “none”, 2, 4 and 8 years). However, the estimated contribution of hospital isolation to the decline of leprosy in Norway ranged from only 3% to 60% for these 8 pairs of assumptions, the other explanation being the socioeconomic development. Thus, the impact of isolation proved to be very uncertain.

“NATURAL EXPERIMENT”

The Norway study showed that declining trends in leprosy transmission may have competing explana-tions. A logical next step in a model-based approach would be a SIMLEP-based analysis of long-term trends in (preferably adjacent) geographical areas with comparable general conditions, but with dif-ferent well documented leprosy control policies. Such trend data would enable disentanglement of competing explanations (MDT, BCG, socioeconomic change) for decreases in transmission, but unfortu-nately they are not readily available. So far, we have not identified suitable datasets.

SCENARIO ANALYSIS OF LEPROSY TRENDS UP TO 2020 USING SIMLEP

The effect of MDT is similar to that of isolation: both prevent leprosy transmission. Trend predictions are complicated by the same factors that were encoun-tered in the evaluation of the Norwegian decline. Building on the Norwegian experience, a scenario analysis of future trends in leprosy incidence was conducted with SIMLEP (20).

For each of the 8 pairs of assumptions on conta-giousness during the incubation period and on


decrease of transmission opportunities, model pro-jections were fitted to reference data on leprosy new case detection from 1985 onwards (the reference case detection rate was calculated as the average of the NCDR of the 14 countries that detected at least 2000 cases in 1998, and for which data are available at country level throughout 1985-1998). In doing so, it was assumed that the delay in case detection decreased in the 1990s, which is in line with the intensification of control efforts that took place in many countries. Subsequently, incidence rates were predicted up to the year 2020, assuming an aver-age detection delay of 2 years from 2000 onwards. Again, wide variation was observed in the projec-tions: the annual decline in incidence rate between 2000 and 2020 ranged from 2% to 8% per year for those pairs of assumptions for which a reasonable fit of the reference data was obtained. The correspond-ing times to reduce the incidence rate by 50% were 43 and 8 years. The rates of decline were lower with contagiousness during the incubation period, and when a faster decrease in transmission opportuni-ties for patients was assumed.

So far, there was no BCG vaccination. The scenar-io analysis was repeated while making quite favour-able assumptions on BCG: 50% lifelong protective efficacy, and rather optimistic coverages. Now, the annual decline in incidence rate ranged from 5% to 10% per year, with corresponding times to reduce the incidence rate by 50% of 14 and 7 years. Thus, leprosy incidence declined in all scenarios consid-ered, and BCG enhanced the declines. The most important conclusion is the slow pace at which the incidence is reduced in all scenarios.

CONCLUSIONS

• MDT based control appears to reduce transmis-sion. The pace of reduction is highly uncertain, but in any case slow. BCG may enhance the pace, but its impact is also uncertain.

• The impact of MDT based control is highly uncertain because of the following unknowns: – the role of close contact in transmission– the speed of transmission– whether, and to what extent, contagiousness

builds up during the incubation period. Research addressing these questions is essential

to narrow down the uncertainty regarding the impact of MDT based control.

• Further progress through SIMLEP requires data which allow for disentanglement of compet-ing explanations (MDT, BCG, socioeconomic change) for downward trends in leprosy trans-mission. This requires the availability of long-term trend data from geographical areas with comparable general conditions, but with differ-ent well documented leprosy control policies.


References

1. Meima A et al. Trends in leprosy case detection rates. International Journal of Leprosy and Other Mycobacterial Diseases, 1997, 65(3):305-19.

2. International Conference on the Elimination of Leprosy. Reaching every patient in every village. Progress towards the elimination of leprosy. Reports from major endemic countries. New Delhi, India, 11-13 October 1996.

3. Progress towards leprosy elimination. Weekly Epidemiological Record, 1997, 72(23):165-72.

4. Progress towards leprosy elimination. Weekly Epidemiological Record, 1998, 73(21):153-60.

5. Global leprosy situation, September 1999. Weekly Epidemiological Record, 1999, 74(38):313-6.

6. Leprosy – global situation. Weekly Epidemiological Record, 2000, 75(28):226-31.

7. Leprosy. Weekly Epidemiological Record, 2001, 76(23):173-9.

8. Fine PE, Smith PG. Vaccination against leprosy – the view from 1996 [editorial]. Leprosy Review, 1996, 67(4):249-52.

9. International Leprosy Association Technical Forum. Report. Leprosy Review, 2002, 73:S1-S62.

10. Fine PE. Leprosy: the epidemiology of a slow bacteri-um [review]. Epidemiologic reviews, 1982;4:161-88.

11. Gupte MD. South India immunoprophylaxis trial against leprosy: relevance of findings in the context of lep-rosy trends. International Journal of Leprosy and Other Mycobacterial Diseases, 2001, 69(2 Suppl):S10-3.

12. Noordeen SK. The epidemiology of leprosy. In: Hastings RC (ed.). Leprosy. Edinburgh, Churchill Livingstone, 1985, pp. 15-30.

13. van Beers SM, Hatta M, Klatser PR. Patient contact is the major determinant in incident leprosy: implications for future control. International Journal of Leprosy and Other Mycobacterial Diseases, 1999, 67(2):119-28.

14. Blake LA et al. Environmental nonhuman sources of leprosy [review]. Reviews of Infectious Diseases, 1987, 9(3):562-77.

15. Reich CV. Leprosy: cause, transmission, and a new the-ory of pathogenesis. Reviews of Infectious Diseases, 1987, 9(3):590-4.

16. Kazda J, Irgens LM, Kolk AH. Acid-fast bacilli found in sphagnum vegetation of coastal Norway contain-ing Mycobacterium leprae-specific phenolic glycolipid-I. International Journal of Leprosy and Other Mycobacterial Diseases, 1990, 58(2):353-7.

17. Klatser PR et al. Detection of Mycobacterium leprae nasal carriers in populations for which leprosy is endemic. Journal of Clinical Microbiology, 1993, 31(11):2947-51.

18. Meima A et al. SIMLEP: a simulation model for leprosy transmission and control. International Journal of Leprosy and Other Mycobacterial Diseases, 1999, 67(3):215-36.

19. Irgens LM. Leprosy in Norway. An epidemiological study based on a national patient registry. Leprosy Review, 1980, 51(Suppl 1):i-xi, 1-130.

20. Meima A et al. Leprosy will not be eliminated by the year 2005: a scenario analysis. Paper submitted to Bulletin of the World Health Organization.


Annex 7 WORKING PAPER: Current status in reactions and nerve damage in leprosy – what next?


CURRENT STATUS IN REACTIONS AND NERVE DAMAGE IN LEPROSY – WHAT NEXT?

Elizabeth P. Sampaio, Maria Cristina F. Pessolani, Milton O. Moraes, Euzenir N. Sarno Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil.

PATHOGENESIS OF REACTIONS AND NERVE DAMAGE IN LEPROSY

Notwithstanding the application of the Th1xTh2 paradigm to the polar spectrum of leprosy (1), the occurrence of reactions provides new insights into the mechanisms of immunological regulation dur-ing host-pathogen interaction. Reactions might, in fact, represent an immune-inflammatory break-through of the steady-state present in a previously unresponsive (multibacillary [MB]) or low respon-sive (MB or paucibacillary [PB]) patient that can temporarily revert to a highly responsive immuno-logical profile and inflammatory condition, at which time the patient’s clinical state could move toward the tuberculoid end of the spectrum. The potential for patients to develop any type of reaction depends on multifactorial variables that would necessari-ly include genetic features, histocompatibility leu-kocyte antigen (HLA) haplotype, immunological background, and bacillary load, among others. This is particularly true in light of the observation that erythema nodosum leprosum (ENL) is most often experienced by lepromatous patients (borderline lepromatous [BL]/lepromatous leprosy [LL] forms), reversal reaction (RR) most often develops in bor-derline borderline (BB) patients, while both types of reaction tend to occur at a similar frequency rate in BL patients (2).

It is widely accepted that up-regulation of the cell mediated immune (CMI) response, which is depen-dent on the expansion of M. leprae-specific T cells, occurs during RR (3). The re-emergence of CMI seems to be related to the breakage of the anergic state that possibly occurs in patients who present a low immune response level (borderline tubercu-loid [BT], BB, and BL patients). RR is, consequently, associated to the up-regulation of IFNγ production leading to granuloma formation, enhanced macro-phage microbicidal activity, and inflammation (4,5). RR patients are able to respond in vitro to M. lep-rae and in vivo to the lepromin skin test, and RR has been associated with enhanced bacterial clearance

(systemic bacterial load) when compared to unre-actional MB patients (6). Nevertheless, this high responsive profile rapidly reverts back to its prior low responsive state.

Do reversal reactions and erythema nodosum leprosum share a common immunological background?

Accumulated evidence suggesting the participation of CMI in ENL includes:

• The positive lymphoproliferative response in conjunction with increased IFNγ production in response to M. leprae in vitro (7).

• The detection of interferon-gamma (IFNγ) and interleukin (IL)-12 mRNA expression in the lesions and blood of reactional patients (8,9).

• The finding that T cells isolated from the lesions and/or blood of leprosy patients have a Th0 or Th1 profile in vitro (10).

• The involvement of activated T cells in the enhanced tumour necrosis factor-alpha (TNFα) production induced in M. leprae-stimulated monocytes through direct cell-cell contact (11).

The occurrence of sequential ENL and RR in one individual patient may indicate further that both types of reaction share a similar immunological background. An identical mRNA cytokine profile was observed in the lesions of this same patient during the course of reaction, although gammadel-ta (γδ) T cells were only present in the RR and not in the ENL lesion (12). Despite the similar immu-nological profile detected in vivo, the histological and clinical features observed in both types of reac-tion are diverse. In fact, in MB leprosy (when res-cue of specific CMI is more easily achieved, as in the borderline forms), immune reactivity is capable of emerging spontaneously (the so-called reactions) and, depending on the number of bacteria, HLA restriction, and spatial/temporal cell type activa-tion, this immune reactivation is clinically observed as either RR or ENL.

It is worth considering that, due to the dynam-ic but rather chaotic regulation of cytokine secre-tion (13,14), even the most subtle activation process may be capable of triggering an exacerbated inflam-matory response. In any case, detection of IFNγ in vitro in response to M. leprae has only been observed in approximately 30% of all ENL patients stud-ied (Sampaio et al., 16th International Leprosy Congress), despite the fact that the majority of RR and ENL patients expressed IFNγ and IL-12 mRNA in the skin while undergoing reaction. The detec-tion of such cytokines in the tissues of patients in the


absence of detectable IFNγ production in vitro raises at least two interesting hypotheses:

• It is possible that a transient IFNγ production by Th2 cells is operative in the lesions of ENL patients in contrast to what, in RR patients, appears to be a more long-term, established production of IFNγ (and TNFα) by Th1 clones. In fact, it has been reported that, in addition to the IL-12-induced differential expression of the β2 subunit of the IL-12 receptor (IL-12Rβ2) on established Th1 cells (15), an induced tempo-rary up-regulation of the IL-12Rβ2 transcripts in Th2 clones may account for the transient pro-duction of IFNγ in cells with an established Th2 phenotype (16). The quantification of IL-12R transcripts as well as of the subtle differences in mRNA expression (IFNγ, TNFα, IL-12) of ENL vs. RR in situ clearly require further investiga-tion.

• An alternative source of IFNγ may originate from the very early components of the innate immune response. Cells from the innate immu-nity (dendritic cells, monocytes, natural killer [NK] cells) shape the nature of the subsequent adaptive T cell response by influencing the cytokine pattern. The activation of NK cells (or γδ T cells) induced by M. leprae together with the production of IFNγ may occur early on fol-lowing antigen-presenting cell (APC) stimu-lation with the concomitant secretion of IL-27, interferon α, and IL-12 (17). IL-12 is a domi-nant factor in driving the development of a Th1 response leading to IFNγ secretion on the part of NK and T cells. In this connection, it has been further demonstrated that IL-27 (an early product of pathogen- or lipopolysaccharide [LPS]-stimulated APC) is capable of eliciting a potent response from naive (but not memo-ry) CD4+ T and NK cells, in conjunction with an early induction of IFNγ (18) that can also occur independently of IL-12. It is also suggest-ed that IL-27, although it may play a role in the rapid initiation of a response to an inflammato-ry challenge, appears to be unnecessary for its maintenance. It is, therefore, plausible to postu-late that, during ENL, IL-27 and/or IL-12 and IL-15 are involved in the early IFNγ release by NK cells (and naive T cells) that are ultimately responsible for directing the immune response not specifically related to the reactivation of memory T cells. Conversely, in RR, besides the aforementioned cytokines, IL-18, which appears to act at a later stage in Th1 development, will induce, in synergy with IL-12, further secre-tion of IFNγ by the differentiated T cells. IL-21 (19) and IL-23 (17,18) may then come into play

in the process of transition to acquired immuni-ty and on the selective activation of memory T cells, respectively (RR).

Hence, the precise role and expression of these newly described mediators in leprosy, and perhaps others still unknown, certainly merit investigative research.

Major points for further investigation

• Which cells are able to release IFNγ during the reactions? CD4, CD8 T cells, NK cells, γδ T cells?

• Kinetics of the cytokine response in RR vs. ENL.• Role of the innate immune response in leprosy

reactions.

Are other mediators related to the enhanced secretion of TNFα and induction of tissue damage during reactions?

Leprosy reaction has been related to the overproduc-tion of TNFα both in vivo and in vitro. Our data and those of others (20-23) have suggested that TNFα is a key mediator in the immunopathology of tissue damage in both RR and ENL. It has been hypoth-esized that the emergence of the innate or acquired immune response in ENL, followed by production of IFNγ, IL-6 and IL-12 in situ, could be synergis-tically involved in the amplification of the inflam-matory response and in the augmented release of TNFα, both locally and systemically (8,24,25).

In our own study, IFNγ was demonstrated to enhance the M. leprae-induced secretion of TNFα and the rate of macrophage apoptosis both in vivo and in vitro (21, Hernandez et al., submitted for publication). On the other hand, it is also possible to postulate that activation of monocytes by LPS-related molecules, through the CD14 receptor and/or the Toll like family of receptors (TLR) required for optimal induction of innate immunity, might be operative. In that sense, the expression and secre-tion of inflammatory mediators will be preferential-ly detected in ENL independently of IFNγ, and will mediate the systemic damaging effects observed during the reaction. Both TNFα and TLR have been implicated in triggering cell death in response to mycobacterial infection, which might be related to bacterial killing as well. Accordingly, M. leprae (sim-ilarly to M. tuberculosis) has recently been shown to induce apoptosis in monocytes (Hernandez et al., submitted for publication) and to activate NF-kappaB transcription factor (Hernandez et al., 16th International Leprosy Congress). In the same study, thalidomide and pentoxifylline, well known TNFα inhibitors, were able to decrease apoptosis in paral-


lel to the diminished TNFα release (26). Moreover, the 19 kDa of M. leprae seems to activate the TLR2 and to induce apoptosis in vitro (Oliveira et al., sub-mitted for publication).

The balance between pro- and anti-inflammato-ry cytokines induced in response to bacterial prod-ucts in vivo seems to be related to the induction and resolution of inflammation in several diseases as well as in leprosy. Follow-up evaluation of cytokine mRNA expression in reactional skin in the dermis (24,25) and epidermis (27) indicated that improve-ment of patients’ clinical symptoms following in vivo administration of anti-inflammatory treat-ment (prednisone, thalidomide, or pentoxifylline) was associated with decreased expression of TNFα, IFNγ, and IL-12 (24,25) mRNAs; on the other hand, worsening of their clinical conditions was correlated to the maintenance/induction of cytokine mRNAs levels, including IL-10 and IL-4. These cytokines might be a contributing factor in the deleterious effects classically attributed to TNFα. The notion that their overwhelming or unbalanced production can contribute to undesirable inflammatory side-effects must be validated. Several data point to IL-12 as playing a critical role in the pathogenesis of Th1-mediated autoimmune diseases (28). Monitoring of cytokine mRNA expression in situ can allow early indication of occurrence and evolution of reactional inflammation in leprosy.

Studies on the kinetics of cytokine production in vitro have revealed that IL-10 is produced later in culture and down-regulates the production of cyto-kines synthesized earlier, as well as its own produc-tion. In addition, IL-10 secretion by monocytes has been shown to be regulated by TNFα. Enhanced TNFα secretion seems to play a key role in the sus-tained inflammatory manifestations during leprosy reactions, and it is postulated that a different pro-file in the kinetics of TNFα and IL-10 released in response to M. leprae might be detected in vitro in reactional versus unreactional patients. Kinetic stud-ies showed early and enhanced M. leprae-induced TNFα production (mRNA and protein) from ENL patients’ cell cultures followed by a delayed IL-10 response (Sampaio et al., in preparation for publi-cation). Hence, the data favour the idea that, in a low responsive patient, IFNγ can overcome patient’s unresponsiveness by inhibiting IL-10 and augment-ing IL-12 production.

In addition to TNFα, several other mediators are most likely involved in the induction of tissue dam-age. The remodelling of extracellular matrix compo-nents requires the action of proteases, among which are matrix metalloproteinases (MMPs), zinc-binding

proteins that appear to be stimulated by cytokines such as IL-1, TNFα, and phorbol esters. MMPs and their inhibitors also play an important role in the tis-sue remodelling which accompanies inflammation, wound healing, tumour invasion, and bone resorp-tion, and have long been implicated as potential contributory factors in the pathogenesis of inflam-matory skin disorders. In leprosy, enhanced mRNA expression of both MMP-2 and MMP-9 (gelatinase proteins) has recently been detected in reactional but not unreactional leprosy tissue (Teles et al., in prepa-ration for publication). Additionally, cytotoxic genes have been implicated in such typical immunopatho-logical events as transplant rejection. Although our preliminary analysis in peripheral blood mononu-clear cells (PBMC) showed no major differences in mRNA expression of granulysin, Fas L, and gran-zyme B among the patients, investigation of perforin mRNA carried out in biopsies showed expression of message in 50% of RR and 100% of ENL, but not in unreactional patients. The data suggest that cytotox-ic T cells are being recruited to the lesion site during the reactional episode and that they (and the MMPs) may well be participating in generation of the tissue damage detected during the reactions.

Although HLA alleles may play a role in controlling development of the type of leprosy, genetic predis-position is only one factor in the complex process leading to disease, the end result of which is prob-ably dependent on the interplay of several host genes. A variety of other immunogenetic polymor-phisms seems to be implicated in human infectious diseases, cytokine genes being the more relevant ones. Notwithstanding the overlapping mechanisms involved in the immune regulation during reaction, it is known that genetic background influences, for example, approximately 60% and 75% of TNFα and IL-10 production, respectively. Polymorphisms in a number of genes (such as IFNγ, IL-10, IL-4, TNFα) and molecules (such as natural resistance associat-ed macrophage protein 1 [NRAMP1], toll-like recep-tor 2, vitamin D receptor) have been described as being associated with protection and susceptibility, and with severity, in leprosy. Such genetic patterns may well explain the differences found in the pro-files of response observed in lepromatous vs. tuber-culoid patients. Single nucleotide polymorphism (SNP) at position -308 (guanine/adenine) within the promoter region of the TNFα gene was associat-ed with the development of lepromatous leprosy in India (29). However, in the Brazilian population, it was demonstrated that controls showed higher fre-quencies of the -308A TNF mutation as compared to leprosy patients as a whole or MB patients (30). In a subsequent study, a stronger lepromin skin test reaction was detected in the PB patient population


(-308A carriers) when compared to the non-carriers (31); even so, among those -308A TNF carriers who experienced continuous skin inflammation (lepro-sy reactions and BCG vaccination), a decreased skin test response was evidenced. The data suggest that TNFα promoter SNPs may influence disease sus-ceptibility and also indicate that a genetic back-ground favouring high levels of TNFα production in vivo may trigger an immunomodulatory after-effect to control the exaggerated response. A role for TNFα in protection in humans was confirmed when the occurrence of tuberculosis (32) (and leprosy [Joyce et al., 16th International Leprosy Congress]) was detected in patients following in vivo inhibi-tion of TNFα production. In patients with reaction, TNFα promoter SNPs could then indicate high or low TNFα production and could be used as prog-nostic markers in preventing strong inflammatory reaction and excessive tissue damage. On the other hand, enhanced levels of TNFα have been noted in the serum of both –308A and –308G carriers in the course of leprosy reaction (33), suggesting that other factors may also be contributing to TNFα hyper-responsiveness. As related to IL-10, it has also been described that the IL-10 haplotypes located in the distal promoter region of the gene appear to be asso-ciated to disease severity in leprosy (Moraes et al., 16th International Leprosy Congress). Altogether, the results indicate that specific cytokine SNPs could be used as susceptibility and severity mark-ers by genetically screening the high risk population among both household contacts and patients, there-by providing a novel tool for predicting susceptibil-ity to disease and/or later complications, such as nerve injury.


• Is TNFα being induced in ENL through an IFNγ independent manner? Toll like receptor? CD14 molecule?

• Definition of risk factors and/or markers for development of reactions.

• Application of anti-TNFα therapy to modu-late the clinical manifestations of reactions/pro-phylactic treatment for reactions (Zafirlukast, infliximab, anti-TNFα antibodies, anti-TNFR antibodies, azathyoprine, cyclosporine, thalido-mide analogues).

NERVE DAMAGE IN LEPROSY

At this particular moment, it is generally agreed that the most fascinating field of leprosy research lies in eludicating the peculiar context in which this par-ticular bacterial infection terminates in such specific

nerve destruction. Nerve damage occurs across the entire spectrum of leprosy but is more often seen at the lepromatous pole, especially among borderline patients, who can present the most extensive nerve impairment. In some cases, irreversible nerve inju-ry progresses insidiously and largely unnoticed for long periods of time, in marked contrast to the acute and/or subacute injury of peripheral nerves that occurs in the course of the reactional states seen in patients undergoing chemotherapy. A find-ing of considerable clinical importance is that many patients, even after terminating MDT and therefore lacking viable M. leprae, nevertheless present signifi-cant nerve damage and persistent neuritis. Whether this is due to dead bacteria or the attempt to clear the bacteria or their components is not clear. Steroid therapy administered prior to the onset of signif-icant nerve damage is often able to prevent these permanent disabling symptoms. However, in some cases, prompt and adequate oral prednisone seems to have very little effect on the recovery of persistent nerve lesions (34).

Several pathogenic mechanisms, including bio-chemical interference of the bacillus with host cell metabolism, mechanical damage due to the large influx of cells and fluid, and/or immunological damage, may be responsible for nerve damage in leprosy. It is known that successful axonal regenera-tion occurs exclusively within the endoneurial tubes lined by Schwann cell (SC) basal laminae, and that degradation and remodelling of extracellular matri-ces are important aspects of the regenerative process (35). Antigen-specific T cell-mediated hypersensitiv-ity to M. leprae antigens, which is more frequently observed during acute reversal reactions, has been associated with the pathogenesis of nerve lesions in the tuberculoid forms of leprosy. However, the mechanism of nerve damage in the lepromatous forms is still uncertain. Because reactions are accom-panied by an increased CMI response, and because acute nerve lesions particularly occur during these episodes, defining the role of the immuno-inflam-matory response deserves particular consideration (36,37). Taking into account that the neural lesion is specifically related to M. leprae infection, the release of some mediators induced by this pathogen would probably account for nerve destruction, either direct-ly or indirectly. Based on the available literature implicating TNFα in the pathological mechanisms of several nervous system diseases, this cytokine has been detected in the sera of both MB (ENL and RR patients) and PB patients with neuritis although, as expected, at lower levels than in ENL (36). Therefore, TNFα has been considered one of the possible prime movers in mediating nerve injury.


How is it that TNFα released within the nerve environment is able to destroy the nerve structure in such a way as to obliterate its regenerative capabilities?

The expression of TNFα mRNA and protein in the skin and nerves of RR patients (23) points to TNFα as participating in the pathophysiology of nerve dam-age in leprosy. Moreover, there is mounting evidence that TNFα contributes to the pathogenesis of such neurological autoimmune diseases as multiple scle-rosis and experimental allergic encephalomyelitis. It has also been pointed out that this cytokine exerts damaging effects on oligodendrocytes, on myelin-producing cells of the central nervous system, and on myelin itself (38,39), and that it plays a key role in augmenting inflammatory demyelination. A combi-nation of TNFα and TGFβ has been reported to cause significant SC detachment and lysis in rat SCs (40) as well as in a human Schwannoma cell line (ST88-14) (Oliveira et al., in preparation for publication). Recent data have also shown the human SC cell line to express the TNF receptor and the TLR, the latter one in primary human SCs as well (Oliveira et al., submitted). In addition, apoptosis of these cells was induced by way of TLR2 stimulation via the lipopro-tein 19kDa of M. leprae.

It is our understanding that the presence of TNFα both inside the SC and close by in the tissue milieu could lead to SC damage. To search for increased expression of TNFα in the tissue (dermis and epi-dermis), therefore, sounds reasonable in spite of its source. The potentially more logical contribution of macrophages, keratinocytes, endothelial cells, SC cells, neutrophils, and even T cells, in the local pro-duction and/or amplification of the TNFα response must be further pursued. Understanding the mecha-nisms involved in the elevated TNFα production in the surrounding tissue, and inside the nerves them-selves, in conjunction with the ability of these cells to experience the effects of TNFα (cell stimulation, cytotoxicity, cell death) will signify a major break-through in solving the problem of the development of disabilities in leprosy.

In addition to the proposed direct effect of TNFα in neural injury across the entire spectrum of lep-rosy, re-emergence of antigen-specific CD4+ T cells has been considered to have a role both in protec-tion as well as in immunopathology. CD4+ T cells are more abundant in the skin lesions of patients in reaction. In this regard, the anatomical location of CD4+ T cells containing cytotoxic granules has been described. Murine SCs have already been shown to function as APCs for CD8+ cytotoxic T cells in a major histocompatibility complex (MHC) class I-restricted, mycobacterial antigen-dependent man-

ner (41). The expression of HLA class II on human SCs has likewise been demonstrated along with the observation that IFNγ and TNFα action as well as M. leprae invasion resulted in the up-regulation of MHC class II by rodent SCs (42,43). Thus, SCs may be actively involved in the immunopathology of leprosy neuritis by presenting M. leprae antigens to cytotoxic T cells (44). As an alternative mechanism, expression of the neural cell adhesion molecule (N-CAM), also called CD56, on both target and effec-tor cells has been hypothesized to be of importance. Besides NK cells, N-CAM expression has also been observed on some CD4+ T cells in relation to mul-tiple sclerosis (45). These cells have been found to be able to kill N-CAM positive oligodendrocytes in an antigen independent manner (46). It has also been revealed that co-adhesion via other molecules (CD54 and CD11a) was essential in establishing tar-get lysis. Such a mechanism may also be involved in leprosy neuritis since cells derived from inflamed neural tissue show increased N-CAM expression when compared to peripheral T cells.

How does M. leprae infection contribute to nerve injury?

It is clear that a crucial initial event in the neurolog-ical manifestations of leprosy is infection of SCs by the bacteria. Substantial progress has been achieved over the last five years regarding the mechanisms involved in the M. leprae attachment to SCs. It has been demonstrated that the bacteria bind specifically to the globular domain of the α2 chain of laminin-2, the most abundant isoform of laminin present in the basal lamina that covers the SC, and that this binding is necessary and sufficient for adherence to the cells (47). Moreover, the laminin receptor α-dystroglycan was shown to serve as the SC receptor for M. leprae (48). Subsequent studies have identified the cation-ic, histone-like protein (Hlp), also known as laminin-binding protein (LBP), and the phenolic glycolipid I (PGL-I), as potential bacterial adhesins involved in SC interaction (49-51). More recently, it has been observed that M. leprae rLBP also has the capabili-ty to bind several collagen isotypes, which indicates an expansion of this protein’s potential role in myco-bacterial pathogenesis by way of its ability to mediate bacterial interaction with other cell types, such as epi-thelial and endothelial cells, as well as different base membranes (Lima et al., 16th International Leprosy Congress). The recent identification and character-ization of M. leprae molecules capable of interacting with extracellular matrix (ECM) components raises interesting speculation as to the existence of alterna-tive mechanisms by which these molecules, in addi-tion to their roles as adhesins, could be contributing to the pathogenicity of nerve damage in leprosy. One


potential mechanism could be the capacity of these molecules to disrupt, via binding competition, the dynamic cross talk between axon-SC units and the surrounding extracellular matrix. In fact, a reason-able explanation for the recently reported demye-lination effect of PGL-I (52) might be its capacity to disrupt the extracellular signals from the laminin-2 to the axon-SC unit. It is well known that the ECM pres-ent in the peripheral nerve system acts as an organiz-er of peripheral nerve tissue and strongly influences SC adhesion, growth, and differentiation as well as regulating axonal growth during development and regeneration (53). Moreover, the basement membrane plays a vital role in promoting the development of the myelinating SC and in stabilizing SC-axon interaction (54). Among its components, laminin-2 in particular seems to be involved in these processes by way of its signalling activity via the dystroglycan complexes present on the SC membrane (55-57). Demyelination defects are observed in laminin-2 deficiencies, such as congenital muscular dystrophy and the dy/dy mouse (58,59), as well as in mutations that affect the structure and/or signalling properties of the recep-tor complexes of basement membrane proteins (60). Likewise, it has recently been reported that a histone-like protein (Hlp) found in a number of pathogenic Streptoccocus species contains stereospecific proper-ties in the binding of basal membrane components of cardiac fibres and the kidneys. This same bind-ing capability may also be related to the pathogene-sis of bacterial-induced tissue inflammation (61). In this context, it seems reasonable to speculate that dur-ing the course of M. leprae nerve colonization, bacteri-al laminin-binding molecules, such as Hlp and PGL-I, accumulate within the nerve basal membrane. These molecules could possibly be released into the tissue during infection as a result of bacterial lysing (dur-ing chemotherapy and/or host immune response), and would, therefore, be responsible for the persis-tent inflammation and delayed sequelae observed as a result of M. leprae endoneural infection. It would appear worthwhile to investigate the validity of this hypothesis since it could represent a significant achievement in the understanding of progressive nerve damage in leprosy. In addition, intracellular events consequent to M. leprae interaction with the nerve have recently been investigated. Intracellular transduction signalling triggered during associa-tion of the bacteria suggests that tyrosine kinases and phosphatidylinositide-3 kinase signals are activated (Alves et al., 16th International Leprosy Congress). These signals are also triggered by the bacteria in human monocytes, and probably represent univer-sal signals generated early on during phagocytosis (62). Additional results suggest that the intracellular niche of M. leprae has an aperinuclear localization in nonacidified vesicles (Lima et al., 16th International

Leprosy Congress). The events occurring in SC/neurone co-culture systems are being addressed by two independent groups. The results of Hagge et al. (16th International Leprosy Congress) suggest, on the contrary to Rambukkana’s data (52), that M. leprae exercises no detrimental effects on SC function, rein-forcing the idea that most of the neuropathy observed in leprosy is likely due to the aggressive immune response to the nerve infection. Moreover, prelimi-nary data from our own group indicate that the effect of M. leprae on global gene expression in the SC line is implicated in very mild alterations as evaluated through the use of differential display polymerase chain reaction (PCR) and DNA microarrays (Tempone et al., 16th International Leprosy Congress).

It is clear that the study of lepromatous vs. tuber-culoid forms is a common generalization of the infection and disease progression since clinical man-ifestations are the outcome of a very slow and com-plicated interaction between the bacterium and the host. In fact, leprosy is not a stable disease in any of its clinical forms. It is then possible that the outcome of M. leprae infection would in any case lead to the resolution of infection following the induction of IL-12, IL-18, TNFα and IFNγ cytokines. However, for some individuals, their genetic background would provide the scenario for a lower initial response (innate and/or specific immunity), allowing for sub-sequent bacterial multiplication and the establish-ment of different levels of non responsiveness that are present across the disease spectrum. Thus, lep-rosy exhibits a unique immunological pattern which is based on complex interactions between cells and secreted factors that may well represent a dynam-ic behaviour. From the point of view of clearing the bacteria, upgrading responses (reactions) might be considered to be beneficial. However, the inflamma-tion in the tissue and the nerve may turn into perma-nent damage and disability, if not treated adequately. Therefore, it is of the upmost importance to pursue new and effective therapeutic interventions capable of promoting axonal regeneration in these patients.


• Mechanism(s) of Schwann cell injury in leprosy: TNFα, cytotoxic T cell, apoptosis, N-CAM–N-CAM interaction.

• The definition of tissue markers as indicative of nerve damage: myelin components, ninjurin, adhesins, ECM components.

• Schwann cell-M. leprae interaction: demyelination, intracellular metabolism, interaction with ECM.

• Establishment of therapeutic interventions for nerve regeneration: MMP inhibitors, inhibitors of apoptosis, TNFα inhibitors, methylcobala-mine, adhesin inhibitors.


References

1. Yamamura M et al. Defining protective responses to pathogens: Cytokine profiles in leprosy lesions. Science, 1991, 254:277-279.

2. Nery JAC et al. Reactional states in multibacillary Hansen disease patients during multidrug therapy. Revista do Instituto de Medicina Tropical de Sao Paulo, 1998, 40:363-370.

3. Laal S, Mishra RS, Nath I. Type I reactions in leprosy: Heterogeneity in T-cell functions related to the background leprosy type. International Journal of Leprosy, 1987, 55:481-487.

4. Yamamura M et al. Cytokine patterns of immunological-ly mediated tissue damage. Journal of Immunology, 1992, 149:1470-1475.

5. Verhagen CE et al. Reversal reaction in borderline lep-rosy is associated with a polarized shift to type 1-like Mycobacterium leprae T cell reactivity in lesional skin: A follow-up study. Journal of Immunology, 1997, 159:4474-4483.

6. Linhares UC. Emergence of cell-mediated immune response in multibacillary leprosy patients with reversal reaction effects patients’ systemic bacillary load. Master’s thesis in Biological Sciences, 2001, FIOCRUZ, Rio de Janeiro, Brazil.

7. Rao RD, Rao PR. (1987) Enhanced cell-mediated immune response in erythema nodosum leprosum reactions of leprosy. International Journal of Leprosy, 1987, 55:36-41.

8. Sreenivasan P et al. Lepromatous leprosy patients show T helper 1-like profile with differential expression of inter-leukin-10 during type 1 and type 2 reactions. Immunology, 1998, 76:357-362.

9. Moraes MO et al. Cytokine gene expression in leprosy: A possible role for IFNγ and IL-12 in reactions (RR and ENL). Scandinavian Journal of Immunology, 1999, 50:541-549.

10. Howe RC et al. Functional heterogeineity among CD4+ T cell clones from blood and skin lesions of lepro-sy patients. Identification of T-cell clones distinct from Th0, Th1 and Th2. Immunology, 1995, 84:585-594.

11. Sampaio EP et al. T cell-monocyte contact enhances TNFα production in response to M. leprae in vitro. Journal of Infectious Diseases, 2000, 182:1463-1472.

12. Moraes MO et al. Sequential erythema nodosum lep-rosum and reversal reaction with similar lesional cytokine mRNA patterns in a borderline leprosy patient. British Journal of Dermatology, 2001, 144:175-181.

13. Callard R, George AJT, Stark J. Cytokines, chaos, and complexity. Immunity, 1999, 11:597-513.

14. Amiot F et al. Mice heterozygous for a deletion of the tumor necrosis factor-α and lymphotoxin-α genes: Biological importance of a nonlinear response of tumor necrosis factor-α to gene dosage. European Journal of Immunology, 1997, 27:1035-1042.

15. Rogge L et al. Selective expression of an interleukin-12 receptor component by human helper 1 cells. Journal of Experimental Medicine, 1997, 185:825-831.

16. Manetti R et al. Interleukin 12 induces stable prim-ing for interferonγ (IFNγ) production during differentiation of human T helper (Th) cells and transient IFN-γ produc-tion in established Th2 cell clones. Journal of Experimental Medicine, 1994, 179:1273-1283.

17. Robinson DS, O’Garra A. Further checkpoints in Th1 development. Immunity, 2002, 16:755-758.

18. Pflanz S et al. IL-27, a heterodimeric cytokine com-posed of EBI3 and p28 protein induces proliferation of naive CD4+ T cells. Immunity, 2002, 16:779-790.

19. Parrish-Novak J et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lym-phocyte function. Nature, 2000, 408:57-63.

20. Sarno EN et al. Serum levels of tumor necrosis factor-alpha and interleukin-1β during leprosy reactional states. Clinical and Experimental Immunology, 1991, 84:103-108.

21. Sampaio EP et al. Prolonged treatment with recom-binant interferon γ induces erythema nodosum leprosum in lepromatous leprosy patients. Journal of Experimental Medicine, 1992, 175:1729-1737.

22. Sampaio EP et al. The influence of thalidomide on the clinical and immunological manifestation of erythema nodosum leprosum. Journal of Infectious Diseases, 1993, 168:408-414.

23. Khanolkar-Young S et al. Tumor necrosis factor-alpha (TNFα) synthesis is associated with the skin and peripheral nerve pathology of leprosy reversal reactions. Clinical and Experimental Immunology, 1995, 99:196-202.

24. Sampaio EP et al. Pentoxifylline decreases in vivo and in vitro tumor necrosis factor (TNFα) production in lepro-matous leprosy patients with erythema nodosum leprosum (ENL). Clinical and Experimental Immunology, 1998, 111:300-308.

25. Moraes MO et al. Anti-inflammatory drugs block cytokine mRNA accumulation in the skin and improve the clinical condition of reactional leprosy patients. Journal of Investigative Dermatology, 2000, 115:1-7.

26. Sampaio EP et al. Management of erythema nodosum leprosum by thalidomide: Thalidomide analogues inhibit M. leprae-induced TNFα production in vitro. Biomedicine and Pharmacotherapy, 2002, 56:13-19.

27. Teles RMB et al. Differential TNFalpha mRNA regula-tion detected in the epidermis of leprosy patients. Archives for Dermatological Research, 2002, 294(8):355-362.


28. Balashov KE et al. Increased interleukin 12 production in progressive multiple sclerosis: Induction by activated CD4+ T cells via CD40 ligand. Proceedings of the National Academy of Sciences of the United States of America, 1997, 94:599-603.

29. Roy S et al. Tumor necrosis factor promoter polymor-phism and susceptibility to lepromatous leprosy. Journal of Infectious Diseases, 1997, 176:530-532.

30. Santos AR et al. Tumor necrosis factor promoter poly-morphism (TNF2) seems to protect against development of severe forms of leprosy in a pilot study in Brazilian patients. International Journal of Leprosy, 2000, 68:325-327.

31. Moraes MO et al. Tumor necrosis factor-α promoter pol-ymorphism TNF2 is associated with a stronger delayed-type hypersensitivity reaction in the skin of borderline tubercu-loid leprosy patients. Immunogenetics, 2001, 53:45-47.

32. Keane J et al. Tuberculosis associated with Infliximab, a tumor necrosis factor α-neutralizing agent. New England Journal of Medicine, 2001, 345:1098-1103.

33. Sarno EN et al. Pathogenesis of nerve damage in lep-rosy: Genetic polymorphism regulates the production of TNFα. Leprosy Review, 2000, 71:S154-160.

34. Van Brakel WH, Khawas IB. Nerve function impair-ment in leprosy: An epidemiological and clinical study – Part 2: Results of steroid treatment. Leprosy Review, 1996, 67:104-118.

35. Ferguson TA, Muir D. MMP-2 and MMP-9 increase the neurite-promoting potential of Schwann cell basal laminae and are upregulated in degenerated nerve. Molecular and Cellular Neurosciences, 2000, 16:157-167.

36. Sarno EN, Sampaio EP. Role of inflammatory cytokines in tissue injury in leprosy. International Journal of Leprosy, 1996, 64:S69-74.

37. Liu J et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nature Medicine, 1998, 4:78-83.

38. Selmaj KW, Raine CS. Tumor necrosis factor medi-ates myelin and oligodendrocyte damage in vitro. Annals of Neurology, 1988, 23:339-346.

39. Ledeen RW, Chakraborty G. Cytokines, signal transduc-tion, and inflammatory demyelination: Review and hypoth-esis. Neurochemical Research, 1998, 23:277-289.

40. Skoff AM et al. TNFα and TGFβ act sinergistically to kill Schwann cells. Journal of Neuroscience Research, 1998, 53:747-756.

41. Steinhoff U et al. Mycobacterium leprae renders Schwann cells and mononuclear phagocytes susceptible or resistant to killer cells. Infection and Immunity, 1991, 59:684-688.

42. Mitchell GW et al. Class II antigen expression in peripheral neuropathies. Journal of the Neurological Sciences, 1991, 102:170-176.

43. Gold R, Tokia KV, Hartung HP. Synergistic effect of IFN-gamma and TNF-alpha on expression of immune mol-ecules and antigen presentation by Schwann cells. Cellular Immunology, 1995, 165:65-70.

44. Spierings E et al. Novel mechanisms in the immu-nopathogenesis of leprosy nerve damage: The role of Schwann cells, T cells and Mycobacterium leprae. Immunology and Cell Biology, 2000, 78:349-355.

45. Vergelli M et al. A novel population of CD4+CD56+ myelin-reactive T cells lyses target cells expressing CD56/neural cell adhesion molecule. Journal of Immunology, 1996, 157:679-685.

46. Antel JP et al. Non-MHC-restricted cell-mediated lysis of human oligodendrocytes in vitro: Relation with CD56 expression. Journal of Immunology, 1998, 160:1606-1611.

47. Rambukkana A et al. Neural targeting of Mycobacterium leprae mediated by the G domain of the laminin-alpha2 chain. Cell, 1997, 88:811-821.

48. Rambukkana A, Yamada H, Zanazzi G. Role of alpha dystroglycan as a Schwann cell receptor for Mycobacterium leprae. Science, 1998, 282:2076-2079.

49. Shimoji Y et al. A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve laminin-2 and mediates Schwann cell invasion. Proceedings of the National Academy of Sciences of the United States of America, 1999, 96:9857-9862.

50. Marques MAM et al. Bacterial and host-derived cationic proteins bind alpha2-laminins and enhance Mycobacterium leprae attachment to human Schwann cells. Microbes and Infection, 2000, 2:1407-1417.

51. Ng V et al. Role of the cell wall phenolic glycolipid-1 in the peripheral nerve predilection of Mycobacterium lep-rae. Cell, 2000, 103:511-524.

52. Rambukkana et al. Contact-dependent demyelination by Mycobacterium leprae in the absence of immune cells. Science, 2000, 296:927-931.

53. Chernousov MA, Carey DJ. Schwann cell extracel-lular matrix molecules and their receptors. Histology and Histopathology, 2000, 15:593-601.

54. Eidridge CF, Bunge MB, Bunge RP. Differentiation of axon-related Schwann cells in vitro 2. Control of myelin formation by basal lamina. Journal of Neuroscience, 1989, 9:625-638.

55. Bunge MB et al. Schwann-cell function depends upon axonal signals and basal lamina components. Annals of the New York Academy of Sciences, 1990, 580:281-287.

56. Bunge RP, Bunge MB. Evidence that contact with con-nective tissue matrix is required for normal interaction between Schwann cells and nerve fibers. Journal of Cell Biology, 1990, 78:943-950.

57. Uziyel Y, Hail S, Cohen J. Influence of laminin-2 on Schwann cell-axon interactions. Glia, 2000, 32:109-121.


Lepr

osy

58. Xu H et al. Murine muscular dystrophy caused by a mutation in the laminin alpha 2 (Lama2) gene. Nature Genetics, 1994, 8:297-302.

59. Matsumura K et al. Peripheral nerve involvement in merosin-deficient congenital muscular dystrophy and dy mouse. Neuromuscular Disorders, 1997, 7:7-12.

60. Boerkoel CF et al. Perlaxin mutations cause necessive Dejerine-Sottas neuropathy. American Journal of Human Genetics, 2001, 68:325-333.

61. Stinson MW at al. Streptococcal histone-like protein: primary structure of HlpA and protein binding to lipotei-choic acid and epithelial cells. Infection and Immunity, 1998, 66:259-265.

62. Lima CS et al. Intracellular signals triggered during association of Mycobacterium leprae and Mycobacterium bovis BCG with human monocytes. Microbial Pathogenesis, 2001, 31:37-45.


Lepr

osy

Annex 8 WORKING PAPER: Elimination of leprosy as a public health problem – current status and challenges ahead


ELIMINATION OF LEPROSY AS A PUBLIC HEALTH PROBLEM – CURRENT STATUS AND CHALLENGES AHEAD

D. DaumerieCommunicable Diseases, World Health Organization, Geneva

A GLIMPSE AT THE HISTORY

The first formal attempt to estimate the global lep-rosy burden was made by WHO in 1966, when the caseload was estimated to be 10 786 000, of whom 60% were not registered for treatment. This figure was updated in 1972 at the marginally lower esti-mate of 10 407 200 cases. In 1977, the WHO Expert Committee, in its fifth report, estimated the case-load to be over 12 million cases, and in 1983, the WHO Study Group on the Epidemiology of Leprosy in Relation to Control referred to an estimate of 11 525 000 cases. Thus 10-12 million cases was the range frequently mentioned in the mid-1980s.

It was obvious by the mid-1970s that the efforts to control leprosy using long duration, even life-long, dapsone monotherapy were failing. This led to the establishment by WHO/TDR of research pro-grammes directed at developing an effective protec-tive vaccine (IMMLEP) and more effective therapy (THELEP). Surveys showed widespread secondary and primary resistance to dapsone, with the preva-lence of secondary resistance ranging from 10 to 386 per 1000 patients, and that for primary resistance as high as 550 per 1000 new patients. Using the analo-

gy with tuberculosis, it was believed that treatment with regimens composed of two or more drugs, each acting by a different antimicrobial mechanism, would prevent relapse with dapsone-resistant M. leprae. The rapid bactericidal action of rifampicin raised hopes that treatment with this drug would be curative. Large-scale multicentre clinical tri-als proved the high efficacy and good tolerability of a once monthly dose of rifampicin. A major line of investigation at the time was comprised of con-trolled clinical trials among patients with lepro-matous leprosy, to examine the efficacy of various combined drug regimens. The long-term follow-up of multibacillary (MB) patients whose treatment had been terminated suggested that the risk of relapse of MB leprosy after termination of chemotherapy, espe-cially with multidrug therapy (MDT), was smaller than had been feared. As a result, it now appeared ethical for THELEP to undertake large-scale field trials of MDT, in which treatment was to be of finite duration and patients with MB leprosy were to be followed for evidence of relapse after treatment had been terminated. Because of its extraordinarily potent bactericidal activity against M. leprae, rifam-picin became an essential component of regimens, and dapsone and clofazimine were included to pre-vent the emergence of rifampicin-resistant M. leprae.

In 1981, WHO convened the Study Group on Chemotherapy for Leprosy Control. The Study Group recommended combined drug regimens based on the supervised intermittent administration of rifampicin for both MB and paucibacillary (PB) leprosy. These WHO “study-group regimens” were then widely implemented.

�

�

�

�

�

�

�

��

��

��

��

��

��

��

��

��

��

��

��

��

��

�

��

��

��

Figure 1. Global prevalence of leprosy


FROM CONTROL TO ELIMINATION AS A PUBLIC HEALTH PROBLEM

Due to the substantial progress in leprosy control achieved by implementing MDT, the World Health Assembly (WHA) in 1991 called for the “elimina-tion of leprosy as a public health problem by the year 2000”, defining elimination as attaining a level of prevalence below 1 case per 10 000 population. The figures and trends at the time suggested that this ambitious goal was feasible. In 1991, global esti-mates of the leprosy burden were revised to 5.3 mil-lion, from the 10-12 million of 1985. This was largely due to the number of patients who had been cured and taken off the registers. It was estimated that about 2-3 million people had residual grade 2 defor-mities.

The elimination strategy had the effect of galvaniz-ing governments, nongovernmental funding agen-cies, and communities. WHO developed the concept of leprosy elimination campaigns (LECs) and spe-cial action programmes for the elimination of lepro-sy (SAPELs) in order to detect and treat all patients, including those in difficult to access geographic

areas. The result was an intensification of leprosy elimination efforts leading to a significant decline in prevalence between 1991 and 1996, before it started to level off and reach the detection level (Fig 1).

In the meantime, there was a steady increase in the number of new cases reported. Global detection was first reported in 1991, with 584 000 new cases detected (Fig. 2). Global detection reached a peak of 820 000 in 1998 and then levelled of at around 750 000 during the following years. WHO attribut-ed this to a number of factors such as the intensified efforts of case detection, high transmission of the disease in certain areas, over-diagnosis or re-regis-tration of previously treated cases, and leprosy elim-ination campaigns (about 50% of cases are attributed to the wide-scale introduction of LECs).

GLOBAL BURDEN OF LEPROSY 1990-2000

Table 1 summarizes global burden of leprosy esti-mates (GBD) for 1990 and 2000.

��

��

��

��

��

��

��

��

��

��

��

��

��

�

��

Figure 2. Global detection

Males Females Persons

YLD(‘000)

GBD1990 171 166 337

GBD2000 58 56 114

YLL(‘000)

GBD1990 23 21 44

GBD2000 19 9 27

DALY(‘000)

GBD1990 194 187 381

GBD2000 77 65 141

Table 1. Global total years of life lost due to disability (YLD), years of life lost (YLL), and disability adjusted life years (DALYs) estimates, 1990 and 2000


WHAT IS THE LEPROSY ELIMINATION STRATEGY?

The strategy for elimination of leprosy as a public health problem is based on early case detection and cure with multidrug therapy. The defined target is to reduce the prevalence, in any given endemic area, to less than one case per 10 000 population. The strategy is based on cer-tain assumptions which need to be understood:

• MDT treatment, together with early case-find-ing, is the best way available today for dealing with the problem of leprosy and its conse-quences.

• The impact of MDT on the disease incidence will be significant only when there are no more “hidden” cases, when MDT coverage reaches optimal levels and is maintained for a number of years.

• As leprosy has a long incubation period and an insidious onset, the impact on transmission will be slow and new cases will continue to appear for several years after elimination levels have been reached.

• The new case detection figure is a poor proxy indicator for incidence and it mainly reflects the operational performance of the programme.

Where do we stand today?

Elimination as defined in the strategy was attained at global level by the end of the year 2000. However, 14 countries were not able to reach the elimination target at national level.

Features of the current global leprosy situation include:

• At the beginning of 2002, the number of leprosy patients was around 635 000, as reported by 106 countries (Table 2). About 760 000 new cases were detected during 2001. Global detection increased in 2001 as compared to 2000 mainly because of a significant increase in detection in India.

• More than 12 million cases had been cured by the beginning of 2002.

• Among newly detected cases, 17% are chil-dren (below the age of 15), 39% are MB based on the clinical classification (more than five skin lesions), 9% are single skin lesion leprosy, and 4% present grade 2 disability at the time of diagnosis.

• The number of relapses remains low, at less than one case per 1000 patients per year.

• No drug resistance following MDT has yet been reported.

• The number of countries showing prevalence rates above 1 per 10 000 population was reduced from 122 in 1985 to 14 at the end of 2001.

• Fewer areas are not covered by MDT. These areas include those which are difficult to access or contain refugee populations, though this remains problematic.

• The gender imbalance has decreased signifi-cantly.

• An increasing number of countries request free supply of MDT drugs.

But this is not the end of the story. This was probably the least difficult part. We are now moving to a far more chal-lenging phase.

Leprosy situation today

Leprosy by type, age, and disability status at the time of detection

In 2000, 115 countries reported 675 180 new cases with classifications (Table 3), out of which 261 713 (39%) were MB, 352 347 (52%) were PB, 61 091 were single lesion (9%), and 29 were of unknown clas-sification. The proportion of MB cases is high in the Eastern Mediterranean, Western Pacific and European Regions (WHO regions), and is particu-larly low in the South-East Asian Region.

Data from 81 countries that reported the proportion of children below 15 years of age among new cases shows that, out of 645 517 cases, 112 327 (17%) were children (Table 4). The proportion of children below 15 years of age among new cases is particularly high in the African and South-East Asia Regions. The average proportion of children among new cases in South-East Asia, excluding India, was 11%. In the

Region Point prevalence

Cases detected during the year

2001

Africa 45 170 39 612

Americas 83 101 42 830

East Mediterranean 7 007 4 758

South East Asia 488 333 668 658

Western Pacific 11 755 7 406

Europe 38 53

World 635 404 763 317

Country details and a map are provided in Annex 8a (page 83).

Table 2.Latest global leprosy situation as reported by 106 countries


Americas, data on the proportion of children among new cases in Brazil were not available at the time of writing and therefore not included, which may have reduced the average at the Regional level; the figure was 9.4% in 1998.

Out of 673 023 new cases with information on their disability status in 94 countries, 24 649 cases (4%) had grade 2 disabilities (Table 5).

The proportion of disabilities among new cases is particularly low in the Americas and South-East Asia. In the Americas, the latest available informa-tion for Brazil is 6%. In South-East Asia, the aver-age proportion of new cases with grade 2 disability, excluding India, is 9%. In the African Region, the rel-atively high proportion of disabilities is attributable to the high detection of new cases and high propor-tion of grade 2 disabilities in Chad, Côte d’Ivoire, Mozambique, and Nigeria.

Table 3: Classification of new cases reported during 2000

WHO Region Number of countries providing

classification

Total number of new cases

classified

MB (%) PB (%) SSPB (%) Unknown

Africa 44 54 572 35 256(65) 19 096(35) 203(0.4) 17

Americas 6 973 624(64) 282(29) 67(7) 0

Eastern Mediterranean 14 5 378 4 329(80) 970(18) 79(2) 0

South East Asia 8 606 671 215 923(36) 330181(54) 60 567(10) 0

Western Pacific 33 7 557 5 557(74) 1816(24) 173(2) 11

Europe 10 29 24(83) 2(7) 2(7) 1

Total: 115 675 180 261 713(39) 352 347(52) 61 091(9) 29

Table 4: Proportion of children under 15 years old among new cases

WHO Region Number of countries providing classification


Children under 15 years old among new cases

(%)

Africa 15 25 256 2 748 11%

Americas 7 1 637 130 8%

Eastern Mediterranean 14 5 412 340 6%

South East Asia 8 606 647 108 513 18%

Western Pacific 30 7 540 594 8%

Europe 7 25 2 8%

Total: 81 645 517 112 327 17%

WHO Region Number of countries providing classification


Disability (%)

Africa 41 52 399 5 827 11%

Americas 6 973 50 5%

Eastern Mediterranean 10 5 412 1 121 21%

South East Asia 8 606 671 16 744 3%

Western Pacific 25 7 543 899 12%

Europe 4 25 8 32%

Total: 94 673 023 24 649 4%

Table 5: Proportion of disabilities among new cases


Is everything going well?

The prevalence of leprosy is still over four times the target level in the six most affected countries – India, Brazil, Madagascar, Mozambique, Myanmar, Nepal. Taken together, these countries represent approxi-mately 90% of the global leprosy burden.

Reasons for the continued high prevalence rates in these countries are varied, most important among them being limited geographical coverage with MDT services and therefore poor access to leprosy diagnosis and treatment. A major operational prob-lem is that leprosy diagnosis and treatment remains a highly centralized activity, often only conducted by specialized staff. In addition, the guidelines fol-lowed in some countries are very rigid and com-plex. Although many policy decisions have been taken by countries to address these problems, their implementation is slow and the impact will not be perceptible for a few years. This in part explains the substantial hidden caseload which still remains and serves as a reservoir of infection, spreading the dis-ease in communities. Other reasons include limited community awareness about the availability of free and effective treatment, and prejudice. These often lead to tragic consequences such as late diagnosis, high disability rates, and low cure rates. Intense fear of leprosy still persists, though to a much lesser extent, at times leading to stigmatization of affected persons and their families.

In addition, some countries facing civil conflicts and eco-nomic turmoil have experienced severe damage to their health infrastructures, affecting all developmental proj-ects.

What is needed is the implementation of a more simplified approach to diagnosis and treatment, using the general health worker at the village level and making services more “patient-friendly” and uncomplicated, so that patients are able to complete the course of treatment with minimum disruption to their daily lives.

MAIN ISSUES ON THE PATH TO LEPROSY ELIMINATION

Detection

The issue of stable, or even increasing, detection in some countries or areas is a major concern and calls for in-depth discussion and analysis. Some experts even interpret the current high detection rate as a failure of the elimination strategy.

With the extension of MDT coverage to previous-

ly uncovered or poorly covered areas, an increase in new cases is not only inevitable but also desir-able. Most of the new cases detected each year are in fact people that developed the overt disease sever-al years earlier, but remained undetected for various reasons, including poor access to leprosy servic-es and ignorance of the availability of a cure. Only a small percentage of newly detected cases are true incident cases i.e. experiencing onset of the disease within the last year. However, for lack of tools, it is impossible to quantify the contribution of incidence to the new case load.

The global leprosy detection trend is indeed par-adoxical. Information coming from some endemic countries clearly shows that, after repeated leprosy elimination campaigns, detection trends are show-ing significant decline. The paradoxical trends with relatively stable detection rates in some major endemic countries (notably India, which contributes 78% of the global annual new case detection) could be the result of several operational and administra-tive shortcomings rather than of epidemiological factors.

Impact of leprosy elimination campaigns on detection trends

The successful implementation of LECs in more than 25 endemic countries has led to the detection and treatment of more than one million cases of leprosy since 1995.

In areas where a single round of campaigns was conduct-ed, annual detection increased significantly in the year the campaign was conducted as compared to preceding years. This peak in annual detection was followed by a decline in subsequent years (i.e. in Hodeidah Governorate of Yemen, Benue, Sokoto and Zamfara States of Nigeria, Binh Thuan Province of Viet Nam, East New Britain District of Papua New Guinea, Kampong Chhnang, Takeo Kampot, Provinces and Kep City of Cambodia, Kosti Province of Sudan). However, this decline in annu-al detection was not observed in other areas such as in the ten districts of Nepal (hilly and terrai areas) and Cebu Province in the Philippines.

In areas where LECs were repeated (Table 6), the total number of cases detected declined in each sub-sequent round, though it was higher compared to years without any special efforts. Over time, the annual detection in some areas even dropped to a level that was much lower than before the start of the campaign. In India, compared to the first round, the total number of new cases detected during the third round declined by 26% in Madhya Pradesh and Chhattisgarh States, 46% in Uttar Pradesh and Uttaranchal Pradesh States, 70% in Bihar and


Jharkhand States, 80% in Orissa and 68% in West Bengal State. Similarly, detection declined by 37% in Mandalay Division of Myanmar and by 43% in the 17 districts of the terrai area in Nepal.

This decline in new cases detected is most likely due to the success of the campaign in effectively clear-ing the backlog of cases. The profile of newly detect-ed patients in subsequent rounds of campaigns also changed. Though the MB proportion among new cases did not change much, the grade 2 disabili-

ties proportion declined significantly as the delay in detection was reduced.

There is, however, concern about those areas where the annual detection rate, even after two or more rounds of campaign, is still around the same level or even higher than before the start of the campaign, in spite of the significant decline in new case detection during each round of the campaign.

The example of India is striking (Fig. 3).

Table 6 Annual detection trends in areas with repeated leprosy elimination campaigns

Area and country (year when LEC was conducted)

Annual case detection

1995 1996 1997 1998 1999 2000 2001

West Bengal State, India.(1998, 1999, 2001)

34 000 27 907 38 134 71 728 54 934 35 666 46 620

Uttar Pradesh State including Uttaranchal Pradesh, India. (1998, 1999, 2001)

59 016 64 640 55 859 107 632 111 436 88 198 114 630

Madhya Pradesh State including Chhattisgarh State, India. (1998, 1999, 2001)

34 538 36 300 31 449 56 319 47 832 41 599 47 072

Orissa State, India.(1997, 1999, 2001)

45 865 42 252 99 341 41 534 65 329 45 216 48 144

Bihar State including Jharkhand State, India.(1997, 1998, 1999, 2001)

51 2 65 99 599 104 478 277 336 172 449 137 172 165 682

Mandalay Division, Myanmar(1998, 1999, 2001)

1 443 1 288 1 585 2 330 5 099 2 301 2 552

17 Districts (terrai areas), Nepal. (1998, 2001) - 4 354 3 791 14 952 5 646 5 751 5 803

Bago District, Myanmar (1997, 1999) 227 228 532 113 372 163 91

Pyay District, Myanmar (1997, 1999, 2001) 276 298 754 146 478 181 149

Hmawbi District, Myanmar (1997, 1999)

167 128 361 100 399 58 50

Shwebo and Wetlet Townships, Myanmar (1998, 1999, 2001)

147 223 142 492 244 188 282

Minbu District, Myanmar (1998, 1999, 2001)

449 351 268 674 560 255 298

Rupandehi District, Nepal (1996, 1998, 2001)

220 612 262 788 282 329 735

��

��

��

��

��

��

��

��

��

��

Figure 3. New leprosy cases detected through

routine and MLEC, India, NLEP 1998-2002

MLEC = Modified leprosy elimination campaigns

NLEP = National Leprosy Elimination Programme


In India, despite the fact that three rounds of large-scale campaigns were conducted, the number of cases detected annually through ‘routine’ leprosy services has remained stable. This could be due to a combination of several factors. One reason could be that the campaigns were not conducted proper-ly and were unable to clear up the huge number of backlog cases present in the area, which were thus left to the routine services to detect. Another reason could be that the increased community awareness and improved service coverage might have encour-aged patients to self-report for treatment after the campaign period. Operational factors such as ful-filling annual detection targets, over-diagnosis and re-registration of old cured cases, could also help explain this paradoxical situation. Continued high transmission and high incidence rates could also contribute to a high annual detection rate in the campaign area.

Sustainable elimination

Integration of leprosy into the general health ser-vices is a key component of the strategy for leprosy elimination. It improves the coverage of leprosy ser-vices and makes them an integral part of the basic health services provided to communities. This is considered to be the most effective method to ensure that the significant gains in leprosy elimi-nation are sustained. We know that new cases will continue to appear for several years, although in reduced numbers, even after the elimination goal has been achieved, due to the long incubation peri-od of the disease. Once the general services assume responsibility for the diagnosis and treatment of lep-rosy, patients will continue to have access to diagno-sis and treatment – even after elimination has been reached.

Specialized leprosy programmes versus integration

Successful integration can only be achieved if the process is well planned, simple and practical. The tasks assigned to general health workers should be clear and in line with their daily routine activities, including the information systems. However, the challenge of integration often lies in managing the interpersonal and human dimensions, which inevitably involves a shift of roles, responsibilities, budgets and power.

It is important to maintain an element of a specialized programme in all endemic countries, either at central level or, in some large countries, at intermediate level. This should provide technical guidance, monitor activi-ties, and evaluate progress towards elimination.

Promoting community action

Community participation in leprosy elimination activi-ties needs to be increased in order to positively change the image of leprosy and reduce the fear of leprosy and the stig-ma attached to the disease. A better understanding of the obstacles to community participation will enable the devel-opment of strategies for promoting community action. Ignorance about the symptoms/signs and curability of the disease are often major problems. The local communi-ty and its leaders should play key roles in improving pub-lic awareness of the signs, symptoms and treatment of the disease, and the availability of free and effective treatment.

Advocacy

Leprosy has always had certain very special features. It is a disease which mainly affects under-served popula-tions and generates intense emotions linked with the age-old stigma against those affected by it. As a result, the fight against leprosy has traditionally been undertaken by a relatively small group of people who, although high-ly dedicated, are often reluctant to share responsibility for the disease and its control with a wider audience. This explains to some extent why the tremendous achieve-ments in leprosy control during the last two decades are not well known, or are even underplayed.

Today we know leprosy to be curable. But making its elimination interesting and attractive to the public, the scientific community, the decision-makers and the politi-cians is not always easy.

However, many countries are now adopting a positive communications approach to change the image of lepro-sy. They are having considerable success using the mass media together with community mobilization

Re-motivating the research community

Nowadays there is an element of desperation within the leprosy research community because epidemio-logical research and studies on new drug develop-ment and diagnosis have largely disappeared. Given our limited arsenal against leprosy, it is fully justifi-able to maintain and support key research activi-ties relevant to elimination and beyond. The priority should be on developing new tools to support elim-ination efforts, in particular to develop tests for lep-rosy exposure (both skin tests and simple blood tests), tests for the prediction of reactions, and bet-ter means of preventing nerve damage. In the long term, research could provide tools for surveillance of transmission and reactivation of disease, detection of non-human sources of infection, and emergence of drug-resistant leprosy strains. Active preventa-tive interventions identified by research would fur-ther help reduce the incidence of leprosy.


In addition, there is a particular need to encourage and strengthen the capacity for epidemiological and opera-tional research.

Standardizing leprosy treatment to a single regimen would also facilitate its integration and ensure the long-term sus-tainability of leprosy control. A uniform MDT regimen for both MB and PB leprosy would be of great advantage.

Prevention of disabilities and rehabilitation

Early detection, treatment with MDT, and management of leprosy reactions is the best strategy for preventing development of deformities. For those who are detected late, simple disability prevention and management com-ponents must be incorporated within leprosy elimination programmes. With ongoing efforts to integrate leprosy services into the general health care services, it is crucial that similar efforts are made to provide disability preven-tion and care services through the general rehabilitative system in the country. To provide special services only for leprosy related disabilities perpetuates stigma, is socially divisive, and is neither cost-effective nor sustainable.

The approach for rehabilitation of those severely affected physically, socially and economically, is to strengthen col-laboration with other relevant services and organizations working in the field.

CURRENT STATUS OF THE ELIMINATION STRATEGY

Although the reduction in prevalence of leprosy is dramatic in historical terms, there is clearly a dis-tinct levelling off in the reduction curve. WHO, in conjunction with the national programmes, has undertaken country-by-country reassessment of the situation and this has often led to policy change. Although the measures are being implemented, results will probably only be visible in a few years time. For example:

• In India, detection rates are among the high-est in the world (about 60 per 100 000 popula-tion). The case detection trend is not showing any appreciable decline, and there is no sin-gle clear explanation for the persistence of this situation in spite of a highly specialized and expensive vertical programme being in opera-tion for close to 50 years. The first problem may lie within the system itself, which burdens the field workers with annual case detection tar-gets and reduces the specificity of diagnosis. Secondly, the reluctance to fully involve the rea-sonably well-developed primary health care system in leprosy elimination activities pre-

vents adequate geographical coverage and lim-its accessibility to MDT services for individual patients. Thirdly, the uneven burden of the dis-ease in the different states of India, and the disparate distribution of resources and activi-ties based on historical attitudes, have resulted in intense activities in certain states and limit-ed activities in others. It is possible that there are other reasons for the confusing detection trends in India. The government, in conjunc-tion with other national and international part-ners, took a bold decision to decentralize the programme and hand over its ownership to the states. In addition, many innovative approach-es are being implemented to bring about a well-planned transition from the current vertical programme to full integration within the well established primary health care system.

• In Madagascar, the significant increase in num-ber of cases detected in recent years cannot be explained just by the intensification of activities. The likely reason for such a constant increase, with a high proportion of MB patients, is the slow expansion of leprosy services to previous-ly uncovered areas. This is further complicated by the current political and economic turmoil. There are hopeful signs that the situation is improving and that political commitment for leprosy elimination will be forthcoming.

• In Brazil, the trend in number of new cases detected is more or less stable or has even increased, as it did after inception of the nation-al programme. However, leprosy elimination campaigns have not contributed significantly to detection of “hidden” cases. The programme is still managed as a highly specialized one with limited stress on integration into the general health services. This is changing with the insti-gation of new initiatives to decentralize leprosy elimination efforts to municipalities, improve community awareness through mass media, and gain high political commitment for elimi-nation efforts.

• In Myanmar, early coverage of the programme was mainly concentrated on a limited num-ber of states/divisions, historically regarded as high endemic areas. Activities in the remaining parts of the country were negligible for vari-ous reasons, including problems of insecuri-ty in the border areas. In recent years however, Myanmar has taken concrete steps to expand MDT service coverage to all states and divi-sions. The programme is fully integrated within the basic health services, with referral and spe-cialized support provided by a handful of ver-tical staff. The country is most likely to achieve the goal of elimination very shortly.


Improving service coverage

The leprosy elimination campaigns conducted in Ethiopia extended coverage of leprosy services to an additional 19 zones covering 650 health facilities. Thus the number of health facilities providing MDT services in Ethiopia increased from 36% to 62% as a result of the campaign activities.

Closing the gender gap

Contrary to expectations, the proportion of female cases among newly detected cases has increased significant-ly during the LECs. Evidence of the gender gap in detec-tion being reduced was observed especially in the state of Madhya Pradesh, India. During the first campaign, the proportion of females among newly detected cases was 31.5%. This increased to 39.1% and 47.6% respective-ly during the second and third campaigns. Similarly in Nepal, the proportion of female cases detected during the LEC was around 40%.

Quality of diagnosis

The LECs have incorporated immediate post-LEC eval-uation to assess the quality of diagnosis and registration practices. Such evaluations have been found to be useful in improving the capacity of health workers and in man-aging MDT services.

• In India, the outcome of the LEC carried out in Jharkhand State was evaluated in six random-ly selected districts covering eight blocks with-in four weeks of completion of the campaign. It was reported that health workers were able to examine 47% of suspected cases identified by the search teams. Upon re-examination of indi-viduals with suspicious skin lesions who had not been screened, 21% were found to have the disease. Among a sample of 267 newly detect-ed PB cases reported during the campaign, 12% were found to be wrongly diagnosed (i.e. not cases of leprosy) and 5% were ‘recycled’ cases (i.e. old cases who had completed treatment, or defaulters who were re-registered as newly detected cases).

Similarly, among 126 newly detected MB cases that were re-examined, 8% had been wrongly diagnosed and 9% were recycled cases. Among 2440 community members who were random-ly interviewed, it was found that 67% were aware of the activities related to the campaign that had been conducted in their village, and 78% knew that drugs to treat leprosy could be obtained from the nearest health centre.

• In Myanmar, the national programme evalu-ated the LEC conducted in Mandalay Division during 2001. As part of the evaluation, 1307 cases that had been newly detected were re-examined. Of these, 20% were found to be wrongly diagnosed.

• In Nepal, similar evaluations were conduct-ed in Parsa, Dhanusha, Mahottari and Kailali Districts. In Kailali District, of 265 newly detect-ed cases who were re-examined, 7.7% were found to be wrongly diagnosed and 2% were recycled cases. In Parsa, of 74 new cases who were re-examined, 23% were found to be wrongly diagnosed and 6.8% recycled cases. Similarly, in Dhanusha and Mahottari Districts, the proportions of newly detected cases wrong-ly diagnosed were 10.1% and 21.9% respective-ly, and the proportions of recycled cases were 9.6% and 15.2%.

Lessons learnt

Projections are being made that there is still a sub-stantial hidden caseload of leprosy, and that the cur-rent detection levels are a failure of the elimination strategy itself. The evidence for this often points to the high numbers of new cases emerging even after repeated LECs. As a result of the successful imple-mentation of LECs in over 25 endemic countries however, more than one million new cases have been detected and treated since 1995. It is one of the main reasons for the increase observed in annu-al detection. In addition to increasing detection, the LECs have also promoted and strengthened the inte-gration of leprosy services with the general health care system. As a result of this, the geographic cov-erage of leprosy services has increased significant-ly in many countries while services at the peripheral level have been sustained. Various public informa-tion activities carried out during the LECs have also increased awareness about the disease, especially at the village and ward levels, and this has, in turn, encouraged individuals with suspicious skin con-ditions to self-report for diagnosis and treatment. The active involvement of various community lead-ers and administrative authorities has also helped increase political commitment, especially in cam-paign areas. While all cases detected during LECs are immediately put on MDT, the active involve-ment of the general health services has made it pos-sible for patients to collect their MDT drugs free of charge at a nearby health facility, saving them the effort of having to travel to a special centre which, for most patients, is some distance from their home.


POSSIBLE SCENARIOS, FROM THE WHO PERSPECTIVE

Sustainable elimination through integration of leprosy control

Compared to almost all other communicable diseas-es, leprosy control is successful. Today the picture is clearer than it was ten years ago. Whatever com-plexity we may introduce in analysing the situation, or in attributing factors that contributed to reach this situation, the fact is that 20 years ago the world had to deal with more than 5 million registered cases and today this number is reduced to less than one million, concentrated in a limited number of countries. We must acknowledge success, and dis-cuss the failures openly as a joint responsibility. The debate on prevalence versus detection/incidence is not very relevant. The fact is that detection over the last few years has been stable at around 0.7 mil-lion. Detection is in fact a ‘prevalence’, and we know nothing about the incidence of the disease (let alone incidence of infection). We do know where we are, that coverage has increased, that MDT is effective, and that there is no threat of drug resistance. The main issue to address today is that of stable detec-tion. Would it be possible to reduce the number of new cases significantly in a limited period of time, or should we make sure that our health systems are sustainable enough to diagnose and treat new cases as long as necessary?

What are the factors contributing to detection, and what actions could be envisaged?

Transmission of leprosy

We all know implicitly that transmission is high in some regions, low in others, and does not exist in many. To compound the difficulty, as in any other communicable disease, transmission is influenced by economic, social, environmental and other fac-tors which make communicable diseases a public health problem. Can we find ways to transform the ‘implicit’ into facts? Can we wait for tools to diag-nose infection, or improve our knowledge on trans-mission? Would it be possible today, using proxy but robust indicators such as detection in children, to identify geographic areas of high transmission? If yes, what action could be taken? BCG? BCG plus campaign to identify hidden cases? Active search of index cases? Chemoprophylaxis?

Coverage with leprosy services

We believe, and have evidence, that coverage has increased significantly over recent years. However,

we also know that some communities still have lit-tle or no access to health services. Together with governments and nongovernmental organizations (NGOs), we should continue to make sure that no community is neglected. Together with increased coverage, we suspect that the sensitivity of the diag-nosis has increased. Shall we change it and increase the specificity? How? What should always remain in our minds is to ensure the best possible coverage. We should make sure that any decrease in detection cannot be attributed to a decrease in activities.

Delay in detection

As mentioned above, detection is a prevalence, the result of incidence multiplied by the delay in detec-tion (minus the self-healing rate between onset and detection). We all know that detection is the crucial point for the patient, and for the chance to interrupt transmission early enough. We all know that, despite many efforts, the delay in detection remains unac-ceptably high at an average of two years. Moreover, when the ‘incidence’ is very low and the number of cases very small, the delay in detection increases considerably, directly resulting in increased propor-tions of multibacillary disease and disability among new cases. The proposed solutions are the integra-tion of leprosy control with information, educa-tion and communication (IEC)/social mobilization. These solutions are not easy to implement, and are always questioned in terms of cost-effectiveness.

High sensitivity and overdiagnosis

Most of the newly detected cases are PB cases (even if a large proportion of them are treated as MB because of the number of skin lesions). Almost all the cases are diagnosed on clinical criteria. This factor is heavily dependent on the skills and moti-vation of the health staff. It is also influenced by the available resources, including the availability of free-of-charge treatment. Moreover, many pro-grammes consider high detection to be an indicator of good performance. High numbers also facilitate the allocation (and mobilization) of resources both from national and international agencies. The time has now come to increase the specificity of diagno-sis. The question is, how to do it without increasing stigma (and re-introducing skin-smears?). Can we provide simple guidelines to ensure that every new case is in fact both “a case” and “new”?

Investigating every new case

The detection of a new case of leprosy, especially in an advanced form, or in a child, or new cases pre-senting disabilities, should be seen as failures, not as successes. Communities and health workers should


investigate why this has happened and take appro-priate action. Leprosy should no longer be seen or accepted as a fatality. Every new case must be declared, and investigated.

Together with actions to be taken with regard to detection, we must continue to ensure the best pos-sible case holding, including management of leprosy reactions. Ideally, each case detected should be cured without disabilities, and without social stigma. This requires flexibility in drug delivery and adequate information and education for both patients and their families. Those unfortunately disabled and/or discriminated against should have access to the best possible care. This requires advocacy, dedica-tion and conviction more than controversy.

A step further: virtual eradication

The question of whether to work actively towards a leprosy eradication strategy is being raised more and more, but the tools currently available and the existing knowledge on the subject do not yet per-mit us to develop such a strategy. If eradication is to be seriously considered, the first step would be to embark on research to develop laboratory tools that can identify “at risk” groups as well as intervention tools to carry out the task.

What would be the cost-effectiveness of this research, particularly in relation to the gains to be made by completely stopping the occurrence of lep-rosy? If the costs of such an eradication strategy prove to be very high, investment in the necessary research could turn out to be questionable.

On the other hand, is the current strategy for the elimination of leprosy, based on a WHO recom-mended multidrug therapy, sufficient to achieve virtual eradication of the disease in the long term? The answer could be ‘yes’ in principle. What would be needed is further intensification of the elimina-tion strategy. However, it is not clear how long this would need to be maintained to achieve virtual eradication or if the present favourable conditions would be sustained for long enough.

The risks of promoting another strategy, for eradica-tion, at this point in time may be to raise unnecessary hopes and divert attention from the ongoing efforts.

WHO phasing out when the elimination target is reached at national levels

In view of other major public health problems and shifts in priorities, WHO and its member states might decide to stop intensive efforts to address the leprosy problem. As long as control is well inte-grated into the general health services, surveillance is organized and treatment available, this approach could be considered appropriate. Experts express concerns that, in this scenario, leprosy would be for-gotten and would re-emerge following the exam-ples of tuberculosis and malaria. We believe that this is very unlikely based on historical experience and taking into account the epidemiology of the disease.

See for example the detection of leprosy in the US shown below (Fig. 4).

�

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

Figure 4.Hansen’s disease (leprosy) – reported cases by year, United States, 1970–2000

Source: CDC


PROPOSED STRATEGY (FOR DISCUSSION)

Beyond the elimination of leprosy as a public health problem

The WHO recommended MDT has had a signifi-cant impact on reducing the global burden of lep-rosy. Although some endemic countries have not yet been able to reduce prevalence to the elimina-tion level, we believe that this is mainly due to oper-ational shortcomings. Moreover, due to the delay in scaling up MDT coverage in these areas, it will take a few years before the epidemiological impact of the current efforts is noticed. WHO should contin-ue supporting the intensive implementation of the elimination strategy and urgently address issues related to detection. After the elimination target has been achieved, national programmes should con-tinue to work towards further reducing the burden of leprosy. Research could support these efforts by developing new tools to address specific problems (see next section). Given the time needed to devel-op new tools, we should start reactivating research now and make the best possible use of the recent sequencing of M. leprae. This opportunity should not be missed.

Proposed research strategy

Technical issues related to the elimination of leprosy

Sub-clinical infection

Over the past 25 years, several immunological tests have suggested that infection with M. leprae is far more common than is evidenced by the number of overt cases of the disease. Factors that influence the occurrence of disease among individuals infected with M. leprae may differ from those that influence the occurrence of the infection itself. More specif-ic and sensitive immunological tools for study-ing infection and the occurrence of disease among infected individuals would permit more reliable assessment of the risk factors for infection and dis-ease.

Extra-human reservoirs

While humans are considered the major host and reservoir of the leprosy bacillus, other reservoirs of infection have also been identified including the armadillo, chimpanzee and mangabey monkey. The epidemiological significance of these findings is unknown but is likely to be very limited.

Impact of HIV epidemic

Unlike tuberculosis, the general consensus is that there is no clear evidence suggesting an associa-tion between HIV infection and leprosy. One possi-ble explanation is that HIV-positive individuals do not survive long enough in a state of severe immu-no-suppression to allow the development of leprosy. Although most investigators believe that the clini-cal manifestations and frequency of relapse do not differ significantly between HIV-negative and HIV-positive leprosy patients, additional information is needed as there are reports suggesting a significant increase of type 1 reaction and neuritis among HIV-positive MB leprosy cases.

Impact of BCG vaccination

Protection against leprosy by BCG vaccination was demonstrated in five large field trials conducted in India, Malawi, Myanmar, Papua New Guinea and Uganda, although the protective effect varied from 20-30% in Myanmar and India to 80% in Uganda. In some studies, the observed protective effect of BCG was significantly greater among individu-als vaccinated at below the age of 15 years. While most investigators believe the effect was primarily against PB leprosy, more detailed analysis suggest-ed that protection against MB leprosy was similar. Results of three vaccine trials conducted recently in India, Malawi and Venezuela are now available. A protective effect of around 50% against leprosy by BCG was confirmed in these trials, and second or repeated doses of BCG offered additional protec-tion. However, the addition of killed M. leprae did not improve the protection afforded by BCG vac-cination. More information is needed before it can be clearly determined whether the decline of lepro-sy incidence observed in certain populations can be attributed, at least partly, to the widespread applica-tion of BCG.

Simulation modelling

Simulation models of leprosy which are based on epidemiological assumptions taken from various data sets are currently under development. These models may be useful for predicting the effects of different interventions on trends in the disease inci-dence and prevalence, including the best and worst scenarios. Although early results suggest that the decline in incidence associated with current inter-ventions may be more gradual than previously expected, further work needs to be done to validate this approach.


Drug resistance

MDT was developed mainly because of the wide-spread emergence of dapsone resistance, and the regimens were designed on the principle that they would be effective against all strains of M. leprae regardless of their susceptibility to dapsone. This assumption has been unequivocally proved by the success of treating several million patients in the field. Hence, whether the global prevalence of dap-sone resistance is increasing or declining is virtually irrelevant to the strategy of eliminating leprosy.

Rifampicin is, however, by far the most bactericid-al drug against M. leprae and will remain the back-bone of MDT regimens in the foreseeable future. Consequently, every effort should be made to pre-vent the emergence of rifampicin-resistant lepro-sy. Fortunately, the relapse rate after MDT is very low, and up to now no rifampicin-resistant case has been detected among patients relapsing after MDT. It is unclear if, and to what extent, the magnitude of rifampicin-resistant leprosy has been underestimat-ed because, for technical and financial reasons, the rifampicin susceptibility test has been performed in only a few research laboratories. To improve sur-veillance for rifampicin resistance, it may be use-ful to establish a genetic method for rapid detection of rifampicin resistant strains of M. leprae at certain regional reference centres.

The success of WHO-recommended MDT and its sig-nificant impact on reducing the global disease burden is likely to have complex consequences on vari-ous sectors involved in the elimination programme. These include leprologists, leprosy institutions, researchers, academicians and NGOs. Arrangements have to be made so that both the human and finan-cial resources needed for the programme are not dis-couraged and diverted at this crucial stage.

Under the leadership of various WHO/TDR scien-tific working groups, leprosy research was highly active during the last two decades and made a tre-mendous contribution to the development of new technologies. Owing to the great success of imple-menting MDT, however, there has been a clear ten-dency in recent years for leprosy research to decline, and this may lead to the stagnation of new tech-nologies or approaches needed to accelerate lepro-sy elimination. WHO actively encourages national governments, scientific communities, internation-al organizations and NGOs to continue leprosy research. Of course, it may not be possible for WHO to address all the research issues on leprosy. Other groups and academics will continue to follow their own research agendas for various reasons (funding,

ongoing projects, academic interests, fellowships, etc). It will not be possible to coordinate these indi-vidual efforts as the objectives of such research may be different and need not be directed towards lepro-sy elimination efforts. WHO could advocate for and coordinate research activities to address the issues outlined below.

Operational issues

• Improving quality of services: acceptability of the services delivered, patient satisfaction, man-agement of leprosy reactions, cost-effectiveness.

• Operational research may be required to improve the implementation of MDT servic-es, especially to address the issues, in some programmes, of poor coverage, gender, accessi-bility, and cure rates.

Issues related to treatment

• Continuation and completion of ongoing mul-ticentre field trials of new regimens. If proved safe and effective, these will provide alternative therapeutic regimens for patients with special needs, including drug-resistant cases. It is like-ly that newer generations of potential antilepro-sy drugs will be available in the near future although it would be prudent to limit testing of these drugs to animal models and short-term clinical trials (using few patients). If found use-ful, these could be kept in reserve for future use.

• Drug resistance: genotypic methods are likely to play a role in diagnosis and monitoring of drug resistance, particularly resistance to rifampicin.

• Management of reactions and nerve damage to prevent the occurrence of disabilities.

Issues related to transmission

• Highly specific and sensitive tests to monitor transmission in the community.

• Better understanding of the nature of protective immunity against leprosy.

• Use of the M. leprae genome information for developing tests for infection, monitoring rifampicin resistance, and probably for research on development of vaccines against leprosy and other mycobacterial diseases.

• Impact of the BCG vaccination in various parts of the world.

Issues related to epidemiological surveillance

• Tools to measure the impact of MDT interven-tion on the disease incidence.

• HIV and leprosy.• Simulation modelling.


CONCLUSION

TDR, in close collaboration with WHO/LEP (the leprosy group), made an essential contribution to the development of MDT and implementation of the elimination strategy. Based on simplified approach-es to case finding at the community level, MDT treatment and epidemiological surveillance, the global elimination strategy has demonstrated itself to be one of the most cost-effective interventions in the public health domain. However the battle is not over yet. Despite these impressive achievements and the soundness of the MDT strategy, WHO is concerned that leprosy prevalence still stands at around 4 per 10 000 in the six most endemic coun-tries, and that these countries represent about 90% of the global leprosy problem.

It is now essential for countries where leprosy still occurs to identify districts or pockets where the prevalence continues to be high and where the com-munity is at higher risk of being infected with M. leprae. The task ahead is formidable and will not be achieved without new approaches. These new approaches can only be developed with the par-ticipation of national programme managers, elim-ination programmes at all levels, and the research community.


Annex 8a Latest information on the leprosy situation at country level by WHO region


Leprosy Situation in Africa*

Country Point Prevalence

Cases detected during the year 2001

Prevalence per 10 000

Detection per 100 000

Angola 4115 2540 3.1 19.1

Benin 278 391 0.4 6.2

Botswana 43 2 0.3 0.1

Burkina Faso 912 836 0.7 6.8

Burundi 364 213 0.5 3.1

Cameroon 1349 486 0.9 3.1

Cape Verde 38 6 0.9 1.4

Central African Republic 455 263 1.2 7.1

Chad 542 407 0.7 5.2

Congo 906 394 3.0 13.0

DR Congo 4584 4980 0.9 9.4

Eritrea 13 6 0.0 0.2

Ethiopia 5022 4523 0.8 7.1

Gabon 53 50 0.4 4.0

Gambia 55 54 0.4 4.0

Ghana 1263 1389 0.6 6.7

Guinea 1416 1689 1.9 22.3

Kenya 197 180 0.1 0.6

Lesotho 10 10 0.0 0.5

Liberia 423 566 1.3 17.0

Mali 659 616 0.6 5.3

Mauritania 49 104 0.2 3.8

Mauritius 0 0 0.0 0.0

Mozambique 6775 5713 3.4 28.5

Namibia 10 10 0.1 0.6

Niger 1348 1353 1.2 12.2

Nigeria 6609 5981 0.6 5.2

Senegal 457 464 0.5 4.8

Seychelles 6 2 0.8 2.6

Tanzania 5235 4656 1.5 13.6

Togo 320 279 0.7 5.9

Uganda 911 685 0.4 3.0

Zambia 753 764 0.8 8.2

Total 45170 39612 0.9 7.9

* Madagascar, one of the six major endemic countries, did not report in 2001


Leprosy Situation in the Americas





Argentina 1766 373 0.5 1.0

Brazil 77676 41070 4.5 23.8

Chile 0 0 0.0 0.0

Colombia 2008 574 0.5 1.3

Ecuador 239 112 0.2 0.9

Guatemala 0 0 0.0 0.0

Nicaragua 55 8 0.1 0.2

Venezuela 1357 693 0.6 2.8

Total 83101 42830 2.6 13.3

Leprosy Situation in South-East Asia





Bangladesh 8537 10740 0.6 8.2

Bhutan 40 19 0.2 0.9

India 439782 617993 4.3 60.1

Indonesia 17259 13286 0.8 6.2

Myanmar 8237 9684 1.8 21.0

Nepal 10657 13830 4.4 56.5

Sri Lanka 1570 2309 0.8 12.1

Thailand 2251 797 0.4 1.3

Total 488333 668658 3.2 43.7

Leprosy Situation in the Eastern Mediterranean Region





Afghanistan 133 22 0.1 0.1

Bahrain 36 7 0.6 1.1

Egypt 2443 1521 0.4 2.2

Iran 391 76 0.1 0.1

Jordan 0 0 0.0 0.0

Morocco 360 74 0.1 0.3

Oman 8 4 0.0 0.2

Pakistan 1350 973 0.1 0.6

Qatar 0 10 0.0 1.6

Saudi Arabia 14 48 0.0 0.2

Somalia 299 211 0.3 2.0

Sudan 1452 1299 0.5 4.3

Yemen 521 513 0.3 2.7

Total 7007 4758 0.2 1.1


Leprosy Situation in the Western Pacific 2001





American Samoa 8 5 1.1 7.0

Brunei 5 5 0.2 1.5

Cambodia 526 634 0.4 4.7

China 3510 1726 0.0 0.1

Cook Islands 0 0 0.0 0.0

Federated States of Micronesia

58 88 4.8 72.7

Fiji 6 4 0.1 0.7

French Polynesia 6 4 0.3 1.7

Guam 1 1 0.1 0.6

Hong Kong 37 10 0.1 0.1

Japan 10 0.0

Kiribati 9 18 1.0 20.2

Korea 581 36 0.1 0.1

Lao People’s Dem. Rep. 200 183 0.4 3.3

Macao 0 0 0.0 0.0

Malaysia 931 195 0.4 0.8

Marshall Islands 52 63 7.9 95.5

Mongolia 0 0 0.0 0.0

Nauru 3 3 2.5 25.0

New Caledonia 17 7 0.8 3.2

New Zeeland 5 2 0.1 0.1

Niue 0 0 0.0 0.0

Northern Mariana Islands 6 5 0.7 6.0

Papua New Guinea 394 369 0.8 7.6

Philippines 3816 2669 0.5 3.4

Samoa 17 13 0.9 7.1

Singapore 28 10 0.1 0.3

Solomon Islands 7 7 0.2 1.7

Tonga 0 0 0.0 0.0

Tuvalu 0 0 0.0 0.0

Vanuatu 2 1 0.1 0.5

Vietnam 1530 1336 0.2 1.7

Total 11755 7404 0.07 0.4


Geographic distribution of leprosy in 2002: prevalence per 10 000 population

2 to

5.3

(4)

1 to

2 (

6)0

to 1

(73

)

Geo

grap

hic

dist

ribu

tion

of l

epro

sy in

200

2: p

reva

lenc

e pe

r 10

000

pop

ulat

ion


Annex 9 WORKING PAPER: Issues related to the intensity of Mycobacterium leprae transmission


ISSUES RELATED TO THE INTENSITY OF MYCOBACTERIUM LEPRAE TRANSMISSION

Paul R. KlatserKIT Biomedical Research, Koninklijk Instituut voor de Tropen/Royal Tropical Institute (KIT), Amsterdam, The Netherlands.

INTRODUCTION

The current strategy for eliminating leprosy is based on the presumption that, once the prevalence is below 1/10 000 at global level, transmission will dwindle and eventually stop (1). This assumption is likely based on the fact that MDT affects the pool of infectious patients, but the question as to wheth-er it affects this pool sufficiently is not yet answered. The major challenge for the leprosy research com-munity in the near future will therefore be to pro-vide evidence that the current strategy of leprosy elimination is feasible, and functions according to expectations.

Using registered prevalence as a proxy indicator for the epidemiology of leprosy has several caveats (2). By definition it only reflects registered cases, and thus obscures the existence of true leprosy patients not reported to the health facilities and of default-ers who are continuously removed from the regis-ters. Inconsistencies in case definition and diagnosis due to changed diagnostic criteria make compari-son of prevalence rates over the years and between programmes difficult if not impossible. The preva-lence used in leprosy control is the point prevalence (taken at a certain moment in time) and not the peri-od prevalence. This rate is affected by the duration of the disease, the more so because patients with a short treatment of less than one year may not be included (at present PB patients; in future maybe also MB patients). Taking the influence of these fac-tors on prevalence into account, it is clear that MDT has had a major impact on prevalence of the disease and will continue to do so in the near future pro-vided that access to care is sustained at the current level.

Incidence would, in principle, be a better measure for monitoring the trends in transmission, but vir-tually no information on incidence rates exists (3,4) nor is it likely to become available considering the difficulties associated with measuring it. Case detec-tion rates (CDR) are available for leprosy, but are far from good indicators of incidence, let alone trans-mission. The CDR may be inflated by backlog cases

and by defaulting and relapse cases, and is heavi-ly influenced by the intensity of case-finding efforts. Trends in the CDR may thus be distorted as a result of bias and confounding. The implications of BCG vaccination, cross-immunization or competing risk by tuberculosis, increased natural immunity, and the HIV pandemic on leprosy incidence, can only be guessed at. CDR trends are, on a global scale, rel-atively stable, while at country level CDRs show a declining, stable or even rising trend.

Because the causative organism of leprosy, Mycobacterium leprae, cannot be cultured in vitro, it is virtually impossible to assess exposure and the onset of infection and disease. As a consequence, the chain of infection, considered as the relationship between M. leprae, transmission and the human host, is poorly understood.

Several studies on the epidemiology of leprosy do however allow us to make at least some inferences about the properties of M. leprae, its host, and the contact patterns between these two, factors that, in concert, determine the ability of leprosy to spread.

THE PATHOGEN

Although M. leprae cannot be cultured in the lab-oratory, and thus cannot be used to meet Koch’s postulates, few people doubt that M. leprae is the cause of infection which leads to leprosy. M. leprae is an obligate intracellular bacterium in the order Actinomycetales. It measures 0.3-0.5 x 4.0-7.0 µm and its optimal growth temperature has been deter-mined to be 30°C. In mice it divides only once in 12 to 14 days, and the bacteria may remain viable for several days outside the body. Until recently, i.e. until the genome sequence became available, most studies on the genetic composition of distinct M. lep-rae isolates failed to yield evidence for the existence of different strains of M. leprae.

The high rate of self healing among persons present-ing with early monomacular lesions suggests that M. leprae is a poor pathogen. The presence of specif-ic immune responses to M. leprae in healthy subjects indirectly suggests that the presence of M. leprae in a human is not associated with disease per se. Whether widespread infection is as common as often thought is questionable. The early indirect proof for this was based on in vitro assays of lymphocyte trans-formation in the presence of M. leprae antigens (5), but these assays were not specific and were liable to confounding. The presence of antibodies to PGL-I is probably specific, but good quality testing often indicates only a relatively low percentage of posi-tives (up to 5%) among very high risk groups such


as household contacts of multibacillary patients (6). Transient nasal carriage of M. leprae in the healthy population, as evidenced by PCR, is not likely to reflect infection but rather environmental contami-nation (7). On the basis of these studies, it is often concluded that M. leprae infection is far more com-mon than believed, thus implicating casual contact as a major factor in transmission, as in tuberculosis. However, this author is of the opinion that there is little evidence for widespread M. leprae infection.

Multibacillary leprosy patients are thought to be a main source of infection, being able to shed large numbers of bacteria from the nose – on average, 107 viable M. leprae per day (8). It is very likely that these patients have already been contagious for a consid-erable length of time before the definite diagnosis. Disability at the time of registration is a well known and common phenomenon illustrating the delay in patient detection (9). Early lepromatous leprosy is often difficult to diagnose because patients may present no lesions and no definite loss of sensation.

If indeed the nose is the port of exit for M. leprae bacteria, transmission is likely mediated by drop-let spread. In contrast to airborne spread through coughing, as in the case of tuberculosis, droplet spread requires close proximity/contact with the host since droplets (defined by a size >5 µm) do not spread more than 1 metre. Such a mode of transmis-sion would well fit the observed contact patterns (see below).

Apart from being a portal of exit, it is also likely that the nose is a portal of entry for the bacteria; this entry may be facilitated by small injuries in the nasal mucosa (10). Experimental transmission of leprosy in nude mice has been demonstrated through nasal inhalation, and was most successful when the nasal tissue had been lightly abraded. It might be worth-while further exploring the role and condition of the nasal mucosa in transmission of, and suscepti-bility to, leprosy. Impairment of nasal function may enhance the development of disease, as is seen in other infectious diseases (11).

The skin has also been considered to be a possible port of exit and entry of leprosy bacteria, most likely due the prominent role it plays in disease manifes-tation. Untreated lepromatous patients are likely to be able to shed large numbers of bacteria from their ulcers or otherwise injured skin. However, since there is no evidence that M. leprae can penetrate intact skin, only accidental inoculation with M. lep-rae would favour the skin as a possible port of entry. Evidence for a possible role of arthropods in trans-mission of leprosy is circumstantial at best (11).

CONTACT PATTERNS

It is often thought that most cases of leprosy arise from the non-contact population, similar to tuber-culosis, where casual contact plays a significant role in transmission. However, the long incubation time in leprosy makes it difficult to obtain contact his-tories. There are now several studies which clearly show that close contact is more important than often believed (12,13). The risk of developing leprosy is greatest among close contacts of leprosy patients, like household contacts, but also neighbours and social contacts, and particularly close contacts of multibacillary patients – the attack rate among per-sons living in the household of a multibacillary patient can be five to ten times as high as among non-contacts. Household contacts of paucibacil-lary patients experience a two-fold risk of develop-ing leprosy disease compared to non-contacts. These findings are a sign that the likelihood of disease var-ies with the degree of contact and with the intensity of the infectious source. However, exposure of both the index case and close contacts to a common envi-ronmental source of infection is theoretically possi-ble as well.

The view that patients are the single source of infec-tion is possibly too narrow. In any case, it is well conceivable that multibacillary leprosy patients, and paucibacillary patients to a lesser extent, are infec-tious long before their clinical diagnosis, since the majority of new cases are only diagnosed years after the onset of disease. This group of patients may pose a serious threat to the control of transmission of leprosy, which is mainly based on case finding. It was previously shown, using the enzyme linked immunosorbent assay (ELISA), that seropositive contacts of leprosy patients have a relative hazard of 8 for developing leprosy, and of 25 for developing MB leprosy, compared to seronegative contacts (14). These results clearly show that serology can be used as a tool to identify contacts of leprosy patients with a high risk of developing leprosy. Screening contacts of leprosy patients in order to find and follow-up or treat those at increased risk of developing the dis-ease may ultimately prevent transmission.

The rarity of secondary cases among contacts of immigrant leprosy patients in non-endemic coun-tries remains puzzling. It could mean that host and/or environment related factors play a prominent role in the transition from infection to disease. Some fac-tors in the chain of contact and transmission (e.g. closeness of contact, skin contact, impairment of nasal integrity by typical concomitant respiratory infections) may be specific to areas of current ende-micity.


PROPERTIES OF THE HOST

The immune status of the host has been implicated as an important factor in the process leading from infection to disease and, to a lesser extent, in trans-mission itself (since we cannot measure infection). The environment can both undermine (through malnourishment, recurrent infections, HIV infec-tion) and boost (through BCG vaccination) the immune system, while innate resistance is deter-mined by genetic determinants.

Genetic studies in leprosy are prone to bias, since families share the same genetic factors as well as the same environmental factors, and it is difficult if not impossible to assess the effect of both factors independently since we cannot yet measure expo-sure to M. leprae. In addition, inconsistencies can occur when examining the genetic determinants of leprosy due to the fact that the genetic mecha-nisms may differ between and within populations. Epidemiological evidence for genetic control of sus-ceptibility to leprosy per se was produced in sev-eral studies, but was equivocal in others, possibly because of heterogeneity of case definition, eth-nic background, or interference of environmental risk factors. The significance of host genetic factors must not be overestimated; individuals with a cer-tain ‘high risk’ histocompatibility leukocyte anti-gen (HLA) type still have a very low risk (generally less than 1%) of developing leprosy or a particular type of leprosy. Environmental and behavioural fac-tors may be of such importance that they obscure genetic involvement. Evidently, genetic predisposi-tion is only one factor in the complex process lead-ing to leprosy.

Similarly, socioeconomic status involves a complex of associated variables and it is difficult to assess the relevance of each variable. The precise mechanism by which socioeconomic factors influence leprosy risk is still unknown and may only be understood when more data on the mechanism and pattern of transmission are available. However, as is true for most infectious diseases, improvement of socio-economic circumstances is an efficacious means for control, if only because it goes along with improved quality and coverage of health services.

BCG vaccination provides protection against lep-rosy, although studies have shown the degree of protection to vary from 20% to 80% (15). BCG immu-nization also leads to a shift in immune response from multibacillary to paucibacillary leprosy (16).

HIV infection suppresses cellular immunity and the disastrous effects of HIV on the incidence of tuber-

culosis have been documented since the mid-1980s. There has been much speculation on the possible epidemiological impact of HIV on the leprosy sit-uation. Several studies have reported conflicting results, but globally there is no indication that the HIV epidemic is leading to a significant increase in the number of leprosy patients. The impact of HIV may be minimal because it simply takes too much time for symptoms to develop from an infection with M. leprae (11).


References

1. Leprosy. Fact sheet no. 101. Geneva, World Health Organization, January 2001.

2. Visschedijk J et al. Mycobacterium leprae – millennium resistant! Leprosy control on the threshold of a new era. Tropical Medicine & International Health, 2000, 5(6):388-99.

3. Fine PEM. Reflections on the elimination of leprosy. International Journal of Leprosy, 1992, 60:71-80.

4. Smith WC. We need to know what is happening to the incidence of leprosy. Leprosy Review, 1997, 68(3):195-200.

5. Godal T, Negassi K. Subclinical infection in leprosy. British Medical Journal, 1973, 3:557-559.

6. Cellona RV et al. Cross-sectional assessment of ELISA reactivity in leprosy patients, contacts, and normal popu-lation using the semisynthetic antigen natural disaccharide octyl bovine serum albumin (ND-O-BSA) in Cebu, The Philippines. International Journal of Leprosy and Other Mycobacterial Diseases, 1993, 61(2):192-8.

7. Hatta M et al. Spatial distribution and persistence of Mycobacterium leprae nasal carriage among a population in which leprosy is endemic in Indonesia. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1995, 89:381-385.

8. Davey TF, Rees RJW. The nasal discharge in leprosy: clinical and bacteriological aspects. Leprosy Review, 1974, 45:121-134.

9. Ferreira J et al. Estimating hidden prevalence in Hansen’s disease through diagnosis delay and grade of disa-bility at time of diagnosis. International Journal of Leprosy and Other Mycobacterial Diseases, 2000, 68(4):464-73.

10. McDermott-Lancaster RD, McDougall AC. Mode of transmission and histology of M. leprae infection in nude mice. International Journal of Experimental Pathology, 1990, 71:689-700.

11. Beers SM van, Wit MYL de, Klatser PR. The epide-miology of Mycobacterium leprae: recent insight. FEMS Microbiology Letters, 1996, 136:221-230.

12. Beers SM van, Hatta M, Klatser PR. (1999) Patient contact is the major determinant in incident leprosy: impli-cations for future control. International Journal of Leprosy, 1999, 67:119-128.

13. Fine PE et al. Household and dwelling contact as risk factors for leprosy in northern Malawi. American Journal of Epidemiology, 1997, 146(1):91-102.

14. Douglas JT et al. A prospective study of seropositivi-ty as a risk factor for development of leprosy among house-hold contacts. Submitted for publication, 2003.

15. Fine PEM. BCG vaccination against tuberculosis and leprosy. British Medical Journal, 1988, 44: 691-703.

16. Chaudhury S et al. An eight-year field trial on anti-leprosy vaccines among high-risk household contacts in Calcutta metropolis. International Journal of Leprosy, 1994, 62:389-394.


Lepr

osy


Lepr

osy

Annex 10 WORKING PAPER: Vaccines for leprosy and other mycobacterial diseases – what do we know today?


VACCINES FOR LEPROSY AND OTHER MYCOBACTERIAL DISEASES – WHAT DO WE KNOW TODAY?

M.D. Gupte, P. Manickam, B. Kishore KumarNational Institute of Epidemiology (Indian Council of Medical Research), Chennai – 31, India.

INTRODUCTION

Vaccines are considered for use against some of the mycobacterial diseases, viz. tuberculosis, leprosy and Buruli ulcer (1). BCG happens to be the vaccine that has been considered for use in all three condi-tions, although several other vaccines – first genera-tion vaccines – have also been tried against leprosy: • Tuberculosis (TB): BCG• Buruli ulcer: BCG• Leprosy: BCG, BCG + killed Mycobacterium

leprae, ICRC, M. w, M. habana

FIELD TRIALS OF BCG FOR LEPROSY

The efficacy of BCG against leprosy has been inves-tigated in several parts of the world (1,2). In trials conducted in India and Malawi (3), the protective efficacy of BCG against leprosy was found to be bet-ter than against tuberculosis, although there was wide variation in the estimates of protective effica-cy against leprosy. Trials in Venezuela and Malawi (4) yielded very similar conclusions: BCG was effec-tive, and repeated doses of BCG conferred addi-tional protection, but the addition of heat-killed M. leprae (HKML) did not offer any additional benefit. The protection offered by BCG was again higher for leprosy than tuberculosis.

In a prospective study in South India (Chingleput), in which the efficacy of BCG against tuberculosis and leprosy was studied, BCG was found to give limited overall protection against leprosy (17% and 24% for two different doses), but no protection against smear positive forms of the disease (Table 1) (2).

MULTI-ARM LEPROSY VACCINE TRIAL IN SOUTH INDIA

During 1991-1998, a concurrent comparison of four candidate vaccines, namely BCG, BCG + HKML, M. w, and ICRC, was undertaken in a vaccine trial in South India (5). The protective efficacy of BCG + HKML and ICRC was in the order of 65% at the sec-ond follow-up survey, 4-8 years after vaccination (Fig. 1). In the Jordan report (6) of the US National Institutes of Health, these findings were considered very important, and further analysis and testing of the ICRC and BCG + HKML candidate vaccines was suggested.

In the trial, about 11% of vaccinated subjects had received prior BCG vaccination. Sub-group analy-sis of subjects who had received prior BCG vaccina-tion compared with subjects who had not received prior BCG vaccination was carried out. The efficacy of the various vaccines was similar in both BCG scar positive and negative groups (unpublished). Vaccine efficacy for different age groups indicated that the vaccines were effective even in previously infected individuals. The third follow-up survey of the vac-cine trial is nearly completed and the results will be available by March 2003. So far in the third follow-up survey, there are about 120 new (provisional) cases in the vaccinated cohort, compared to over 600 and 300 cases in the first and second follow-up surveys respectively, indicating possible overall reduction of leprosy in the cohort population (unpublished).

0.1 mg BCG* 0.01 mg BCG* Placebo P value

Number of new cases 3213 3497 4238

Incidence rate per 1000 6.6 7.2 8.8 < 0.001Protective efficacy % 24.4

( 20.9, 27.8 )17.4

(-21.0, 13.6)

Number of smear positive new cases 40 39 42

Incidence rate per 1000 0.082 0.081 0.087 0.8Protective efficacy % 5.1 7.1

( - 46.3, 38.5 ) ( -43.7, 39.9)

* Numbers in parentheses are 95% confidence intervals

Table 1. Incidence of leprosy and protective efficacy of BCG by dose in a leprosy prevention trial in Chingleput, South India


MODEL PREDICTIONS

Our recent work with a simulation model for lepro-sy predicted that the introduction of a vaccine with 65% protective efficacy against leprosy could bring about a dramatic decline of leprosy incidence (7).

BCG AND TUBERCULOSIS

BCG is known to work against tuberculosis by pre-venting primary infection. How it works against the other diseases is not clear.

Ginsberg commented in a recent article (8) that BCG was developed as a vaccine against TB in the first two decades of the 20th century, but still, 70 years later, it is the only available vaccine against TB. Several trials have been conducted worldwide to evaluate the efficacy of BCG in protecting against tuberculosis; results have shown this to vary from 0% to approximately 80% (1,9,10).

Fine et al (1) have reviewed the findings related to the protective efficacy of BCG for tuberculosis and lepro-sy; the summary information is reproduced in Fig. 2.

ISSUES FOR VACCINE TRIALS IN THE FUTURE

Presently several new vaccines are being developed against tuberculosis, and new information is becom-ing available for both M. tuberculosis and M. leprae. Perhaps the only way to expect new developments in leprosy vaccines is to link efforts with tuberculo-sis in developing newer vaccines.

The main issues to be addressed in designing new vaccine trials for mycobacterial diseases include the incidence of disease, sensitivity and specificity of diagnostic tools, availability of surrogate markers, possible negative effect of the vaccine, operational difficulties, and ethical issues (3,11).

Low incidence of the disease would have implica-tions for sample size, and subjects would have to be followed up for a longer period. The magnitude of confounding of the vaccine efficacy estimates would depend on diagnostic validity in the field situation. Another serious and controversial issue is that of a negative effect of the vaccine, which is clearer when the control arm happens to be a placebo arm, as has been observed in leprosy vaccine trials with all the vaccine candidates (not statistically significant) in the initial follow-up survey (up to 21⁄2 years after vaccination) (12). Finally, the operational and ethical issues involved must be considered in the context of available information on the protective efficacy of the various vaccine candidates before embarking on the conduct of trials of second generation vaccines.

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

Figure 1. Overall vaccine efficacy estimates during the second follow-up of a multi-arm leprosy vaccine trial in South India, 1998


��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

�

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

�

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

��

Figu

re 2

. Est

imat

es o

f BCG

eff

icac

y ag

ains

t di

ffer

ent

form

s of

tub

ercu

losi

s an

d le

pros

y fr

om o

bser

vati

onal

and

exp

erim

enta

l stu

dies

con

duct

ed w

orld

wid

e*

* So

urce

: Fin

e PE

M e

t al

., 19

99 (

1)

|

**

Stud

ies

of p

ulm

onar

y di

seas

e in

chi

ldre

n

|

CT

= cl

inic

al t

rial

C

C =

case

con

trol

stu

dy

CO

H =

coh

ort

stud

y

HH

= h

ouse

hold

con

tact

stu

dy


References

1. Fine PEM et al. Issues relating to the use of BCG in immunization programmes: discussion document. Geneva, World Health Organization, Department of Vaccines and Biologicals, 1999.

2. Gupte MD. Field trials of anti-leprosy vaccines [editori-al]. Indian Journal of Leprosy, 1998, 70(4):363-367.

3. Gupte MD. Field trial of leprosy vaccines. In: Raghunath D, Nayak R, eds. Trends in malaria and vaccine research: the current Indian scenario. New Delhi, Tata McGraw-Hill, 2002:250-259.

4. Gupte MD. Vaccine trials in leprosy – Venezuela, Malawi and India. International Journal of Leprosy, 1999, 67(Suppl):S32-S37.

5. Gupte MD et al. Comparative leprosy vaccine trial in South India. Indian Journal of Leprosy, 1998, 70(4):369-388.

6. Accelerated development of vaccines. USA, National Institutes of Health, Jordan Report, 2000:26.

7. Gupte MD et al. Modeling epidemiology of Leprosy. Indian Journal of Leprosy, 2000, 72(3):305-315.

8. Ginsberg AM. What is new in tuberculosis vaccines? Bulletin of the World Health Organization, 2002, 80(6):483-488.

9. Colidtz GA et al. Efficacy of BCG vaccine in the preven-tion of tuberculosis. Meta-analysis of the published litera-ture. Journal of the American Medical Association, 1994, 271:698-702.

10. Colidtz GA et al. The efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the pre-vention of tuberculosis: meta-analyses of the published literature. Pediatrics, 1995, 96:29-35.

11. Gupte MD, Sampath DK. Ethical issues considered in Tamilnadu leprosy vaccine trial. Issues in Medical Ethics, 2000,VIII(1):10-12.

12. Gupte MD. South India immunoprophylaxis trial against leprosy: relevance of the findings in the context of trends in leprosy. Workshop proceedings. Leprosy Review, 2000, 71(Suppl.):S43-S49.

Leprosy · Group on Chemotherapy for Leprosy Control, which recommended combined-drug regimens...

Documents

Transcript of Leprosy · Group on Chemotherapy for Leprosy Control, which recommended combined-drug regimens...