160 Leprosy.Id2

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

56 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 57 ELIMINATION OF LEPROSY AS gy with tuberculosis, it was believed that treatment A PUBLIC HEALTH PROBLEM with regimens composed of two or more drugs, each acting by a different antimicrobial mechanism, – CURRENT STATUS AND would prevent relapse with dapsone-resistant M. CHALLENGES AHEAD leprae. The rapid bactericidal action of rifampicin raised hopes that treatment with this drug would be curative. Large-scale multicentre clinical tri- D. Daumerie als proved the high efficacy and good tolerability Communicable Diseases, of a once monthly dose of rifampicin. A major line World Health Organization, Geneva of investigation at the time was comprised of con- trolled clinical trials among patients with lepromatous leprosy, to examine the efficacy of various combined drug regimens. The long-term follow-up A GLIMPSE AT THE HISTORY of multibacillary (MB) patients whose treatment had been terminated suggested that the risk of relapse of The first formal attempt to estimate the global lep- MB leprosy after termination of chemotherapy, espe- rosy burden was made by WHO in 1966, when the cially with multidrug therapy (MDT), was smaller caseload was estimated to be 10 786 000, of whom than had been feared. As a result, it now appeared 60% were not registered for treatment. This figure ethical for THELEP to undertake large-scale field was updated in 1972 at the marginally lower esti- trials of MDT, in which treatment was to be of finite mate of 10 407 200 cases. In 1977, the WHO Expert duration and patients with MB leprosy were to be Committee, in its fifth report, estimated the case- followed for evidence of relapse after treatment load to be over 12 million cases, and in 1983, the had been terminated. Because of its extraordinarily WHO Study Group on the Epidemiology of Leprosy potent bactericidal activity against M. leprae, rifam- in Relation to Control referred to an estimate of picin became an essential component of regimens, 11 525 000 cases. Thus 10-12 million cases was and dapsone and clofazimine were included to pre- the range frequently mentioned in the mid-1980s. vent the emergence of rifampicin-resistant M. leprae. It was obvious by the mid-1970s that the efforts In 1981, WHO convened the Study Group on to control leprosy using long duration, even life- Chemotherapy for Leprosy Control. The Study long, dapsone monotherapy were failing. This led Group recommended combined drug regimens to the establishment by WHO/TDR of research pro- based on the supervised intermittent administration grammes directed at developing an effective protec- of rifampicin for both MB and paucibacillary (PB) tive vaccine (IMMLEP) and more effective therapy leprosy. These WHO “study-group regimens” were (THELEP). Surveys showed widespread secondary then widely implemented. and primary resistance to dapsone, with the prevalence 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-

Figure 1. Global prevalence of �� leprosy � � � � � � �

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58 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 59 Figure 2. Global detection

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FROM CONTROL TO ELIMINATION areas. The result was an intensification of leprosy AS A PUBLIC HEALTH PROBLEM elimination efforts leading to a significant decline in prevalence between 1991 and 1996, before it started Due to the substantial progress in leprosy control to level off and reach the detection level (Fig 1). achieved by implementing MDT, the World Health Assembly (WHA) in 1991 called for the “elimina- In the meantime, there was a steady increase in the tion of leprosy as a public health problem by the number of new cases reported. Global detection year 2000”, defining elimination as attaining a level was first reported in 1991, with 584 000 new cases of prevalence below 1 case per 10 000 population. detected (Fig. 2). Global detection reached a peak The figures and trends at the time suggested that of 820 000 in 1998 and then levelled of at around this ambitious goal was feasible. In 1991, global esti- 750 000 during the following years. WHO attribut- mates of the leprosy burden were revised to 5.3 mil- ed this to a number of factors such as the intensified lion, from the 10-12 million of 1985. This was largely efforts of case detection, high transmission of the due to the number of patients who had been cured disease in certain areas, over-diagnosis or re-regis- and taken off the registers. It was estimated that tration of previously treated cases, and leprosy elim- about 2-3 million people had residual grade 2 defor- ination campaigns (about 50% of cases are attributed mities. to the wide-scale introduction of LECs).

The elimination strategy had the effect of galvaniz- ing governments, nongovernmental funding agen- GLOBAL BURDEN OF LEPROSY cies, and communities. WHO developed the concept 1990-2000 of leprosy elimination campaigns (LECs) and spe- Table 1 summarizes global burden of leprosy esti- cial action programmes for the elimination of lepro- mates (GBD) for 1990 and 2000. sy (SAPELs) in order to detect and treat all patients, including those in difficult to access geographic

Table 1. Males Females Persons Global total years YLD(‘000) of life lost due to GBD1990 171 166 337 disability (YLD), years of life lost GBD2000 58 56 114 (YLL), and disability YLL(‘000) adjusted life years GBD1990 23 21 44 (DALYs) estimates, GBD2000 19 9 27 1990 and 2000 DALY(‘000) GBD1990 194 187 381 GBD2000 77 65 141

58 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 59 WHAT IS THE LEPROSY • At the beginning of 2002, the number of leprosy ELIMINATION STRATEGY? patients was around 635 000, as reported by 106 countries (Table 2). About 760 000 new cases The strategy for elimination of leprosy as a public health were detected during 2001. Global detection problem is based on early case detection and cure with increased in 2001 as compared to 2000 mainly multidrug therapy. The defined target is to reduce the because of a significant increase in detection in prevalence, in any given endemic area, to less than one India. case per 10 000 population. The strategy is based on cer- • More than 12 million cases had been cured by tain assumptions which need to be understood: the beginning of 2002. • Among newly detected cases, 17% are chil- • MDT treatment, together with early case-find- dren (below the age of 15), 39% are MB based ing, is the best way available today for dealing on the clinical classification (more than five with the problem of leprosy and its conse- skin lesions), 9% are single skin lesion leprosy, quences. and 4% present grade 2 disability at the time of • The impact of MDT on the disease incidence diagnosis. will be significant only when there are no more • The number of relapses remains low, at less “hidden” cases, when MDT coverage reaches than one case per 1000 patients per year. optimal levels and is maintained for a number • No drug resistance following MDT has yet been of years. reported. • As leprosy has a long incubation period and an • The number of countries showing prevalence insidious onset, the impact on transmission will rates above 1 per 10 000 population was reduced be slow and new cases will continue to appear from 122 in 1985 to 14 at the end of 2001. for several years after elimination levels have • Fewer areas are not covered by MDT. These been reached. areas include those which are difficult to access • The new case detection figure is a poor proxy or contain refugee populations, though this indicator for incidence and it mainly reflects the remains problematic. operational performance of the programme. • The gender imbalance has decreased significantly. Where do we stand today? • An increasing number of countries request free Elimination as defined in the strategy was attained supply of MDT drugs. at global level by the end of the year 2000. However, 14 countries were not able to reach the elimination But this is not the end of the story. This was probably the target at national level. least difficult part. We are now moving to a far more chal- lenging phase. Features of the current global leprosy situation include: Leprosy situation today Leprosy by type, age, and disability status at the time of detection In 2000, 115 countries reported 675 180 new cases Table 2. with classifications (Table 3), out of which 261 713 Latest global leprosy situation as reported by (39%) were MB, 352 347 (52%) were PB, 61 091 were 106 countries single lesion (9%), and 29 were of unknown classification. The proportion of MB cases is high in Region Point Cases detected the Eastern Mediterranean, Western Pacific and prevalence during the year 2001 European Regions (WHO regions), and is particularly low in the South-East Asian Region. Africa 45 170 39 612 Americas 83 101 42 830 Data from 81 countries that reported the proportion East Mediterranean 7 007 4 758 of children below 15 years of age among new cases South East Asia 488 333 668 658 shows that, out of 645 517 cases, 112 327 (17%) were Western Pacific 11 755 7 406 children (Table 4). The proportion of children below Europe 38 53 15 years of age among new cases is particularly high World 635 404 763 317 in the African and South-East Asia Regions. The average proportion of children among new cases Country details and a map are provided in Annex 8a (page 83). in South-East Asia, excluding India, was 11%. In the

60 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 61 Table 3: Classification of new cases reported during 2000

WHO Region Number of Total number MB (%) PB (%) SSPB (%) Unknown countries of new cases providing classified classification 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 Total number of Children under 15 years old (%) providing classification new cases 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%

Table 5: Proportion of disabilities among new cases

WHO Region Number of countries Total number of Disability (%) providing classification new cases 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%

Americas, data on the proportion of children among The proportion of disabilities among new cases is new cases in Brazil were not available at the time of particularly low in the Americas and South-East writing and therefore not included, which may have Asia. In the Americas, the latest available informa- reduced the average at the Regional level; the figure tion for Brazil is 6%. In South-East Asia, the aver- was 9.4% in 1998. age proportion of new cases with grade 2 disability, excluding India, is 9%. In the African Region, the rel- Out of 673 023 new cases with information on their atively high proportion of disabilities is attributable disability status in 94 countries, 24 649 cases (4%) to the high detection of new cases and high propor- had grade 2 disabilities (Table 5). tion of grade 2 disabilities in Chad, Côte d’Ivoire, Mozambique, and Nigeria.

60 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 61 Is everything going well? ly uncovered or poorly covered areas, an increase in new cases is not only inevitable but also desir- The prevalence of leprosy is still over four times the able. Most of the new cases detected each year are in target level in the six most affected countries – India, fact people that developed the overt disease sever- Brazil, Madagascar, Mozambique, Myanmar, Nepal. al years earlier, but remained undetected for various Taken together, these countries represent approxi- reasons, including poor access to leprosy servic- mately 90% of the global leprosy burden. es and ignorance of the availability of a cure. Only a small percentage of newly detected cases are true Reasons for the continued high prevalence rates in incident cases i.e. experiencing onset of the disease these countries are varied, most important among within the last year. However, for lack of tools, it is them being limited geographical coverage with impossible to quantify the contribution of incidence MDT services and therefore poor access to leprosy to the new case load. diagnosis and treatment. A major operational problem is that leprosy diagnosis and treatment remains The global leprosy detection trend is indeed par- a highly centralized activity, often only conducted adoxical. Information coming from some endemic by specialized staff. In addition, the guidelines fol- countries clearly shows that, after repeated leprosy lowed in some countries are very rigid and com- elimination campaigns, detection trends are show- plex. Although many policy decisions have been ing significant decline. The paradoxical trends taken by countries to address these problems, their with relatively stable detection rates in some major implementation is slow and the impact will not be endemic countries (notably India, which contributes perceptible for a few years. This in part explains the 78% of the global annual new case detection) could substantial hidden caseload which still remains and be the result of several operational and administra- serves as a reservoir of infection, spreading the dis- tive shortcomings rather than of epidemiological ease in communities. Other reasons include limited factors. community awareness about the availability of free and effective treatment, and prejudice. These often Impact of leprosy elimination campaigns lead to tragic consequences such as late diagnosis, high disability rates, and low cure rates. Intense on detection trends fear of leprosy still persists, though to a much lesser The successful implementation of LECs in more than 25 extent, at times leading to stigmatization of affected endemic countries has led to the detection and treatment persons and their families. of more than one million cases of leprosy since 1995.

In addition, some countries facing civil conflicts and eco- In areas where a single round of campaigns was conduct- nomic turmoil have experienced severe damage to their ed, annual detection increased significantly in the year health infrastructures, affecting all developmental proj- the campaign was conducted as compared to preceding ects. years. This peak in annual detection was followed by a decline in subsequent years (i.e. in Hodeidah Governorate What is needed is the implementation of a more of Yemen, Benue, Sokoto and Zamfara States of Nigeria, simplified approach to diagnosis and treatment, Binh Thuan Province of Viet Nam, East New Britain using the general health worker at the village level District of Papua New Guinea, Kampong Chhnang, and making services more “patient-friendly” and Takeo Kampot, Provinces and Kep City of Cambodia, uncomplicated, so that patients are able to complete Kosti Province of Sudan). However, this decline in annu- the course of treatment with minimum disruption to al detection was not observed in other areas such as in the their daily lives. ten districts of Nepal (hilly and terrai areas) and Cebu Province in the Philippines. MAIN ISSUES ON THE PATH TO In areas where LECs were repeated (Table 6), the LEPROSY ELIMINATION total number of cases detected declined in each subsequent round, though it was higher compared to Detection years without any special efforts. Over time, the annual detection in some areas even dropped to a The issue of stable, or even increasing, detection in level that was much lower than before the start of some countries or areas is a major concern and calls the campaign. In India, compared to the first round, for in-depth discussion and analysis. Some experts the total number of new cases detected during the even interpret the current high detection rate as a third round declined by 26% in Madhya Pradesh failure of the elimination strategy. and Chhattisgarh States, 46% in Uttar Pradesh and Uttaranchal Pradesh States, 70% in Bihar and With the extension of MDT coverage to previous-

62 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 63 Table 6 Annual detection trends in areas with repeated leprosy elimination campaigns

Area and country Annual case detection (year when LEC was conducted) 1995 1996 1997 1998 1999 2000 2001 West Bengal State, India. 34 000 27 907 38 134 71 728 54 934 35 666 46 620 (1998, 1999, 2001) Uttar Pradesh State including Uttaranchal 59 016 64 640 55 859 107 632 111 436 88 198 114 630 Pradesh, India. (1998, 1999, 2001) Madhya Pradesh State including Chhattisgarh 34 538 36 300 31 449 56 319 47 832 41 599 47 072 State, India. (1998, 1999, 2001) Orissa State, India. 45 865 42 252 99 341 41 534 65 329 45 216 48 144 (1997, 1999, 2001) Bihar State including Jharkhand State, India. 51 2 65 99 599 104 478 277 336 172 449 137 172 165 682 (1997, 1998, 1999, 2001) Mandalay Division, Myanmar 1 443 1 288 1 585 2 330 5 099 2 301 2 552 (1998, 1999, 2001) 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 167 128 361 100 399 58 50 (1997, 1999) Shwebo and Wetlet Townships, Myanmar 147 223 142 492 244 188 282 (1998, 1999, 2001) Minbu District, Myanmar 449 351 268 674 560 255 298 (1998, 1999, 2001) Rupandehi District, Nepal 220 612 262 788 282 329 735 (1996, 1998, 2001)

Jharkhand States, 80% in Orissa and 68% in West ties proportion declined significantly as the delay in Bengal State. Similarly, detection declined by 37% in detection was reduced. Mandalay Division of Myanmar and by 43% in the 17 districts of the terrai area in Nepal. There is, however, concern about those areas where the annual detection rate, even after two or more This decline in new cases detected is most likely due rounds of campaign, is still around the same level or to the success of the campaign in effectively clear- even higher than before the start of the campaign, in ing the backlog of cases. The profile of newly detect- spite of the significant decline in new case detection ed patients in subsequent rounds of campaigns also during each round of the campaign. changed. Though the MB proportion among new cases did not change much, the grade 2 disabili- The example of India is striking (Fig. 3).

Figure 3. �� New leprosy cases �� detected through routine and MLEC, �� India, NLEP �

� �� 1998-2002 � � �

� ��

� �� MLEC = Modified leprosy elimination campaigns �� NLEP = National Leprosy � Elimination Programme ��

62 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 63 In India, despite the fact that three rounds of large- Promoting community action scale campaigns were conducted, the number of Community participation in leprosy elimination activi- cases detected annually through ‘routine’ leprosy ties needs to be increased in order to positively change the services has remained stable. This could be due to image of leprosy and reduce the fear of leprosy and the stig- a combination of several factors. One reason could ma attached to the disease. A better understanding of the be that the campaigns were not conducted proper- obstacles to community participation will enable the devel- ly and were unable to clear up the huge number of opment of strategies for promoting community action. backlog cases present in the area, which were thus Ignorance about the symptoms/signs and curability of left to the routine services to detect. Another reason the disease are often major problems. The local communi- could be that the increased community awareness ty and its leaders should play key roles in improving pub- and improved service coverage might have encour- lic awareness of the signs, symptoms and treatment of the aged patients to self-report for treatment after the disease, and the availability of free and effective treatment. campaign period. Operational factors such as ful- filling annual detection targets, over-diagnosis and re-registration of old cured cases, could also help Advocacy explain this paradoxical situation. Continued high Leprosy has always had certain very special features. It transmission and high incidence rates could also is a disease which mainly affects under-served popula- contribute to a high annual detection rate in the tions and generates intense emotions linked with the age- campaign area. old stigma against those affected by it. As a result, the fight against leprosy has traditionally been undertaken Sustainable elimination by a relatively small group of people who, although highly dedicated, are often reluctant to share responsibility for Integration of leprosy into the general health ser- the disease and its control with a wider audience. This vices is a key component of the strategy for leprosy explains to some extent why the tremendous achieve- elimination. It improves the coverage of leprosy ser- ments in leprosy control during the last two decades are vices and makes them an integral part of the basic not well known, or are even underplayed. health services provided to communities. This is considered to be the most effective method to Today we know leprosy to be curable. But making its ensure that the significant gains in leprosy elimi- elimination interesting and attractive to the public, the nation are sustained. We know that new cases will scientific community, the decision-makers and the politi- continue to appear for several years, although in cians is not always easy. reduced numbers, even after the elimination goal has been achieved, due to the long incubation peri- However, many countries are now adopting a positive od of the disease. Once the general services assume communications approach to change the image of lepro- responsibility for the diagnosis and treatment of lep- sy. They are having considerable success using the mass rosy, patients will continue to have access to diagno- media together with community mobilization sis and treatment – even after elimination has been reached. Re-motivating the research community Specialized leprosy programmes versus Nowadays there is an element of desperation within integration the leprosy research community because epidemiological research and studies on new drug develop- Successful integration can only be achieved if the process ment and diagnosis have largely disappeared. Given is well planned, simple and practical. The tasks assigned our limited arsenal against leprosy, it is fully justifi- to general health workers should be clear and in line with able to maintain and support key research activi- their daily routine activities, including the information ties relevant to elimination and beyond. The priority systems. However, the challenge of integration often lies should be on developing new tools to support elim- in managing the interpersonal and human dimensions, ination efforts, in particular to develop tests for lep- which inevitably involves a shift of roles, responsibilities, rosy exposure (both skin tests and simple blood budgets and power. tests), tests for the prediction of reactions, and better means of preventing nerve damage. In the long It is important to maintain an element of a specialized term, research could provide tools for surveillance of programme in all endemic countries, either at central transmission and reactivation of disease, detection level or, in some large countries, at intermediate level. of non-human sources of infection, and emergence This should provide technical guidance, monitor activi- of drug-resistant leprosy strains. Active preventa- ties, and evaluate progress towards elimination. tive interventions identified by research would further help reduce the incidence of leprosy.

64 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 65 In addition, there is a particular need to encourage and vents adequate geographical coverage and lim- strengthen the capacity for epidemiological and opera- its accessibility to MDT services for individual tional research. patients. Thirdly, the uneven burden of the disease in the different states of India, and the Standardizing leprosy treatment to a single regimen would disparate distribution of resources and activi- also facilitate its integration and ensure the long-term sus- ties based on historical attitudes, have resulted tainability of leprosy control. A uniform MDT regimen for in intense activities in certain states and limit- both MB and PB leprosy would be of great advantage. ed activities in others. It is possible that there are other reasons for the confusing detection Prevention of disabilities and trends in India. The government, in conjunc- rehabilitation tion with other national and international part- ners, took a bold decision to decentralize the Early detection, treatment with MDT, and management programme and hand over its ownership to the of leprosy reactions is the best strategy for preventing states. In addition, many innovative approach- development of deformities. For those who are detected es are being implemented to bring about a well- late, simple disability prevention and management com- planned transition from the current vertical ponents must be incorporated within leprosy elimination programme to full integration within the well programmes. With ongoing efforts to integrate leprosy established primary health care system. services into the general health care services, it is crucial • In Madagascar, the significant increase in num- that similar efforts are made to provide disability preven- ber of cases detected in recent years cannot be tion and care services through the general rehabilitative explained just by the intensification of activities. system in the country. To provide special services only for The likely reason for such a constant increase, leprosy related disabilities perpetuates stigma, is socially with a high proportion of MB patients, is the divisive, and is neither cost-effective nor sustainable. slow expansion of leprosy services to previously uncovered areas. This is further complicated The approach for rehabilitation of those severely affected by the current political and economic turmoil. physically, socially and economically, is to strengthen col- There are hopeful signs that the situation is laboration with other relevant services and organizations improving and that political commitment for working in the field. leprosy elimination will be forthcoming. • In Brazil, the trend in number of new cases CURRENT STATUS OF THE detected is more or less stable or has even ELIMINATION STRATEGY increased, as it did after inception of the national programme. However, leprosy elimination Although the reduction in prevalence of leprosy is campaigns have not contributed significantly to dramatic in historical terms, there is clearly a dis- detection of “hidden” cases. The programme is tinct levelling off in the reduction curve. WHO, still managed as a highly specialized one with in conjunction with the national programmes, has limited stress on integration into the general undertaken country-by-country reassessment of health services. This is changing with the insti- the situation and this has often led to policy change. gation of new initiatives to decentralize leprosy Although the measures are being implemented, elimination efforts to municipalities, improve results will probably only be visible in a few years community awareness through mass media, time. For example: and gain high political commitment for elimination efforts. • In India, detection rates are among the high- • In Myanmar, early coverage of the programme est in the world (about 60 per 100 000 popula- was mainly concentrated on a limited num- tion). The case detection trend is not showing ber of states/divisions, historically regarded as any appreciable decline, and there is no sin- high endemic areas. Activities in the remaining gle clear explanation for the persistence of this parts of the country were negligible for vari- situation in spite of a highly specialized and ous reasons, including problems of insecuri- expensive vertical programme being in opera- ty in the border areas. In recent years however, tion for close to 50 years. The first problem may Myanmar has taken concrete steps to expand lie within the system itself, which burdens the MDT service coverage to all states and divi- field workers with annual case detection tar- sions. The programme is fully integrated within gets and reduces the specificity of diagnosis. the basic health services, with referral and spe- Secondly, the reluctance to fully involve the rea- cialized support provided by a handful of ver- sonably well-developed primary health care tical staff. The country is most likely to achieve system in leprosy elimination activities pre- the goal of elimination very shortly.

64 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 65 Improving service coverage • In Myanmar, the national programme evaluated the LEC conducted in Mandalay Division The leprosy elimination campaigns conducted in during 2001. As part of the evaluation, 1307 Ethiopia extended coverage of leprosy services to cases that had been newly detected were re- an additional 19 zones covering 650 health facilities. examined. Of these, 20% were found to be Thus the number of health facilities providing MDT wrongly diagnosed. services in Ethiopia increased from 36% to 62% as a • In Nepal, similar evaluations were conduct- result of the campaign activities. ed in Parsa, Dhanusha, Mahottari and Kailali Districts. In Kailali District, of 265 newly detect- Closing the gender gap ed cases who were re-examined, 7.7% were Contrary to expectations, the proportion of female cases found to be wrongly diagnosed and 2% were among newly detected cases has increased significant- recycled cases. In Parsa, of 74 new cases who ly during the LECs. Evidence of the gender gap in detec- were re-examined, 23% were found to be tion being reduced was observed especially in the state of wrongly diagnosed and 6.8% recycled cases. Madhya Pradesh, India. During the first campaign, the Similarly, in Dhanusha and Mahottari Districts, proportion of females among newly detected cases was the proportions of newly detected cases wrong- 31.5%. This increased to 39.1% and 47.6% respectively diagnosed were 10.1% and 21.9% respectively during the second and third campaigns. Similarly in ly, and the proportions of recycled cases were Nepal, the proportion of female cases detected during the 9.6% and 15.2%. LEC was around 40%. Lessons learnt Quality of diagnosis Projections are being made that there is still a sub- The LECs have incorporated immediate post-LEC eval- stantial hidden caseload of leprosy, and that the cur- uation to assess the quality of diagnosis and registration rent detection levels are a failure of the elimination practices. Such evaluations have been found to be useful strategy itself. The evidence for this often points to in improving the capacity of health workers and in man- the high numbers of new cases emerging even after aging MDT services. repeated LECs. As a result of the successful implementation of LECs in over 25 endemic countries • In India, the outcome of the LEC carried out in however, more than one million new cases have Jharkhand State was evaluated in six random- been detected and treated since 1995. It is one of ly selected districts covering eight blocks with- the main reasons for the increase observed in annu- in four weeks of completion of the campaign. It al detection. In addition to increasing detection, the was reported that health workers were able to LECs have also promoted and strengthened the inte- examine 47% of suspected cases identified by gration of leprosy services with the general health the search teams. Upon re-examination of indi- care system. As a result of this, the geographic cov- viduals with suspicious skin lesions who had erage of leprosy services has increased significant- not been screened, 21% were found to have the ly in many countries while services at the peripheral disease. Among a sample of 267 newly detect- level have been sustained. Various public informa- ed PB cases reported during the campaign, 12% tion activities carried out during the LECs have also were found to be wrongly diagnosed (i.e. not increased awareness about the disease, especially at cases of leprosy) and 5% were ‘recycled’ cases the village and ward levels, and this has, in turn, (i.e. old cases who had completed treatment, encouraged individuals with suspicious skin con- or defaulters who were re-registered as newly ditions to self-report for diagnosis and treatment. detected cases). The active involvement of various community leaders and administrative authorities has also helped Similarly, among 126 newly detected MB cases increase political commitment, especially in cam- that were re-examined, 8% had been wrongly paign areas. While all cases detected during LECs diagnosed and 9% were recycled cases. Among are immediately put on MDT, the active involve- 2440 community members who were random- ment of the general health services has made it pos- ly interviewed, it was found that 67% were sible for patients to collect their MDT drugs free of aware of the activities related to the campaign charge at a nearby health facility, saving them the that had been conducted in their village, and effort of having to travel to a special centre which, 78% knew that drugs to treat leprosy could be for most patients, is some distance from their home. obtained from the nearest health centre.

66 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 67 POSSIBLE SCENARIOS, we also know that some communities still have lit- FROM THE WHO PERSPECTIVE tle or no access to health services. Together with governments and nongovernmental organizations (NGOs), we should continue to make sure that no Sustainable elimination through community is neglected. Together with increased integration of leprosy control coverage, we suspect that the sensitivity of the diag- Compared to almost all other communicable diseas- nosis has increased. Shall we change it and increase es, leprosy control is successful. Today the picture the specificity? How? What should always remain is clearer than it was ten years ago. Whatever com- in our minds is to ensure the best possible coverage. plexity we may introduce in analysing the situation, We should make sure that any decrease in detection or in attributing factors that contributed to reach cannot be attributed to a decrease in activities. this situation, the fact is that 20 years ago the world had to deal with more than 5 million registered Delay in detection cases and today this number is reduced to less than As mentioned above, detection is a prevalence, the one million, concentrated in a limited number of result of incidence multiplied by the delay in detec- countries. We must acknowledge success, and dis- tion (minus the self-healing rate between onset and cuss the failures openly as a joint responsibility. The detection). We all know that detection is the crucial debate on prevalence versus detection/incidence point for the patient, and for the chance to interrupt is not very relevant. The fact is that detection over transmission early enough. We all know that, despite the last few years has been stable at around 0.7 mil- many efforts, the delay in detection remains unac- lion. Detection is in fact a ‘prevalence’, and we know ceptably high at an average of two years. Moreover, nothing about the incidence of the disease (let alone when the ‘incidence’ is very low and the number of incidence of infection). We do know where we are, cases very small, the delay in detection increases that coverage has increased, that MDT is effective, considerably, directly resulting in increased propor- and that there is no threat of drug resistance. The tions of multibacillary disease and disability among main issue to address today is that of stable detec- new cases. The proposed solutions are the integration. Would it be possible to reduce the number of tion of leprosy control with information, educa- new cases significantly in a limited period of time, tion and communication (IEC)/social mobilization. or should we make sure that our health systems are These solutions are not easy to implement, and are sustainable enough to diagnose and treat new cases always questioned in terms of cost-effectiveness. as long as necessary? High sensitivity and overdiagnosis What are the factors contributing to detection, and what actions could be envisaged? Most of the newly detected cases are PB cases (even if a large proportion of them are treated as Transmission of leprosy MB because of the number of skin lesions). Almost all the cases are diagnosed on clinical criteria. This We all know implicitly that transmission is high in factor is heavily dependent on the skills and moti- some regions, low in others, and does not exist in vation of the health staff. It is also influenced by many. To compound the difficulty, as in any other the available resources, including the availability communicable disease, transmission is influenced of free-of-charge treatment. Moreover, many pro- by economic, social, environmental and other fac- grammes consider high detection to be an indicator tors which make communicable diseases a public of good performance. High numbers also facilitate health problem. Can we find ways to transform the the allocation (and mobilization) of resources both ‘implicit’ into facts? Can we wait for tools to diag- from national and international agencies. The time nose infection, or improve our knowledge on trans- has now come to increase the specificity of diagno- mission? Would it be possible today, using proxy sis. The question is, how to do it without increasing but robust indicators such as detection in children, stigma (and re-introducing skin-smears?). Can we to identify geographic areas of high transmission? provide simple guidelines to ensure that every new If yes, what action could be taken? BCG? BCG plus case is in fact both “a case” and “new”? campaign to identify hidden cases? Active search of index cases? Chemoprophylaxis? Investigating every new case

Coverage with leprosy services The detection of a new case of leprosy, especially in an advanced form, or in a child, or new cases pre- We believe, and have evidence, that coverage has senting disabilities, should be seen as failures, not as increased significantly over recent years. However, successes. Communities and health workers should

66 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 67 investigate why this has happened and take appro- On the other hand, is the current strategy for the priate action. Leprosy should no longer be seen elimination of leprosy, based on a WHO recom- or accepted as a fatality. Every new case must be mended multidrug therapy, sufficient to achieve declared, and investigated. virtual eradication of the disease in the long term? The answer could be ‘yes’ in principle. What would Together with actions to be taken with regard to be needed is further intensification of the elimina- detection, we must continue to ensure the best pos- tion strategy. However, it is not clear how long this sible case holding, including management of leprosy would need to be maintained to achieve virtual reactions. Ideally, each case detected should be cured eradication or if the present favourable conditions without disabilities, and without social stigma. This would be sustained for long enough. requires flexibility in drug delivery and adequate information and education for both patients and The risks of promoting another strategy, for eradica- their families. Those unfortunately disabled and/ tion, at this point in time may be to raise unnecessary or discriminated against should have access to the hopes and divert attention from the ongoing efforts. best possible care. This requires advocacy, dedica- tion and conviction more than controversy. WHO phasing out when the elimination target is reached at national levels A step further: virtual eradication In view of other major public health problems and The question of whether to work actively towards shifts in priorities, WHO and its member states a leprosy eradication strategy is being raised more might decide to stop intensive efforts to address and more, but the tools currently available and the the leprosy problem. As long as control is well inte- existing knowledge on the subject do not yet per- grated into the general health services, surveillance mit us to develop such a strategy. If eradication is is organized and treatment available, this approach to be seriously considered, the first step would be to could be considered appropriate. Experts express embark on research to develop laboratory tools that concerns that, in this scenario, leprosy would be for- can identify “at risk” groups as well as intervention gotten and would re-emerge following the exam- tools to carry out the task. ples of tuberculosis and malaria. We believe that this is very unlikely based on historical experience and What would be the cost-effectiveness of this taking into account the epidemiology of the disease. research, particularly in relation to the gains to be made by completely stopping the occurrence of lep- See for example the detection of leprosy in the US rosy? If the costs of such an eradication strategy shown below (Fig. 4). prove to be very high, investment in the necessary research could turn out to be questionable.

Figure 4. �� Hansen’s disease (leprosy) – �� reported cases by ��

year, United States, � �

1970–2000 � ��

Source: CDC � ��

� ��

68 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 69 PROPOSED STRATEGY Impact of HIV epidemic (FOR DISCUSSION) Unlike tuberculosis, the general consensus is that there is no clear evidence suggesting an associa- Beyond the elimination of leprosy tion between HIV infection and leprosy. One possi- as a public health problem 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. The WHO recommended MDT has had a signifi- Although most investigators believe that the clini- cant impact on reducing the global burden of lep- cal manifestations and frequency of relapse do not rosy. Although some endemic countries have not differ significantly between HIV-negative and HIV- yet been able to reduce prevalence to the elimina- positive leprosy patients, additional information is tion level, we believe that this is mainly due to oper- needed as there are reports suggesting a significant ational shortcomings. Moreover, due to the delay in increase of type 1 reaction and neuritis among HIV- scaling up MDT coverage in these areas, it will take positive MB leprosy cases. a few years before the epidemiological impact of the current efforts is noticed. WHO should contin- Impact of BCG vaccination ue supporting the intensive implementation of the elimination strategy and urgently address issues Protection against leprosy by BCG vaccination was related to detection. After the elimination target has demonstrated in five large field trials conducted in been achieved, national programmes should con- India, Malawi, Myanmar, Papua New Guinea and tinue to work towards further reducing the burden Uganda, although the protective effect varied from of leprosy. Research could support these efforts by 20-30% in Myanmar and India to 80% in Uganda. developing new tools to address specific problems In some studies, the observed protective effect of (see next section). Given the time needed to devel- BCG was significantly greater among individu- op new tools, we should start reactivating research als vaccinated at below the age of 15 years. While now and make the best possible use of the recent most investigators believe the effect was primarily sequencing of M. leprae. This opportunity should against PB leprosy, more detailed analysis suggest- not be missed. ed that protection against MB leprosy was similar. Results of three vaccine trials conducted recently in Proposed research strategy India, Malawi and Venezuela are now available. A protective effect of around 50% against leprosy by Technical issues related to the elimination BCG was confirmed in these trials, and second or of leprosy repeated doses of BCG offered additional protec- Sub-clinical infection tion. However, the addition of killed M. leprae did not improve the protection afforded by BCG vac- Over the past 25 years, several immunological tests cination. More information is needed before it can have suggested that infection with M. leprae is far be clearly determined whether the decline of lepro- more common than is evidenced by the number of sy incidence observed in certain populations can be overt cases of the disease. Factors that influence the attributed, at least partly, to the widespread applica- occurrence of disease among individuals infected tion of BCG. with M. leprae may differ from those that influence the occurrence of the infection itself. More specif- Simulation modelling ic and sensitive immunological tools for study- ing infection and the occurrence of disease among Simulation models of leprosy which are based on infected individuals would permit more reliable epidemiological assumptions taken from various assessment of the risk factors for infection and dis- data sets are currently under development. These ease. models may be useful for predicting the effects of different interventions on trends in the disease inci- Extra-human reservoirs dence and prevalence, including the best and worst scenarios. Although early results suggest that the While humans are considered the major host and decline in incidence associated with current inter- reservoir of the leprosy bacillus, other reservoirs ventions may be more gradual than previously of infection have also been identified including the expected, further work needs to be done to validate armadillo, chimpanzee and mangabey monkey. The this approach. epidemiological significance of these findings is unknown but is likely to be very limited.

68 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 69 Drug resistance ongoing projects, academic interests, fellowships, etc). It will not be possible to coordinate these indi- MDT was developed mainly because of the wide- vidual efforts as the objectives of such research may spread emergence of dapsone resistance, and the be different and need not be directed towards lepro- regimens were designed on the principle that they sy elimination efforts. WHO could advocate for and would be effective against all strains of M. leprae coordinate research activities to address the issues regardless of their susceptibility to dapsone. This outlined below. assumption has been unequivocally proved by the success of treating several million patients in the Operational issues field. Hence, whether the global prevalence of dapsone resistance is increasing or declining is virtually • Improving quality of services: acceptability of irrelevant to the strategy of eliminating leprosy. the services delivered, patient satisfaction, management of leprosy reactions, cost-effectiveness. Rifampicin is, however, by far the most bactericid- • Operational research may be required to al drug against M. leprae and will remain the back- improve the implementation of MDT servic- bone of MDT regimens in the foreseeable future. es, especially to address the issues, in some Consequently, every effort should be made to pre- programmes, of poor coverage, gender, accessi- vent the emergence of rifampicin-resistant lepro- bility, and cure rates. sy. Fortunately, the relapse rate after MDT is very low, and up to now no rifampicin-resistant case has Issues related to treatment been detected among patients relapsing after MDT. • Continuation and completion of ongoing mul- It is unclear if, and to what extent, the magnitude of ticentre field trials of new regimens. If proved rifampicin-resistant leprosy has been underestimat- safe and effective, these will provide alternative ed because, for technical and financial reasons, the therapeutic regimens for patients with special rifampicin susceptibility test has been performed needs, including drug-resistant cases. It is like- in only a few research laboratories. To improve sur- ly that newer generations of potential antilepro- veillance for rifampicin resistance, it may be use- sy drugs will be available in the near future ful to establish a genetic method for rapid detection although it would be prudent to limit testing of of rifampicin resistant strains of M. leprae at certain these drugs to animal models and short-term regional reference centres. clinical trials (using few patients). If found useful, these could be kept in reserve for future use. The success of WHO-recommended MDT and its sig- • Drug resistance: genotypic methods are likely to nificant impact on reducing the global disease burden play a role in diagnosis and monitoring of drug is likely to have complex consequences on vari- resistance, particularly resistance to rifampicin. ous sectors involved in the elimination programme. • Management of reactions and nerve damage to These include leprologists, leprosy institutions, prevent the occurrence of disabilities. researchers, academicians and NGOs. Arrangements have to be made so that both the human and finan- Issues related to transmission cial resources needed for the programme are not dis- couraged and diverted at this crucial stage. • Highly specific and sensitive tests to monitor transmission in the community. Under the leadership of various WHO/TDR scien- • Better understanding of the nature of protective tific working groups, leprosy research was highly immunity against leprosy. active during the last two decades and made a tre- • Use of the M. leprae genome information for mendous contribution to the development of new developing tests for infection, monitoring technologies. Owing to the great success of imple- rifampicin resistance, and probably for research menting MDT, however, there has been a clear ten- on development of vaccines against leprosy and dency in recent years for leprosy research to decline, other mycobacterial diseases. and this may lead to the stagnation of new tech- • Impact of the BCG vaccination in various parts nologies or approaches needed to accelerate lepro- of the world. sy elimination. WHO actively encourages national governments, scientific communities, internation- Issues related to epidemiological surveillance al organizations and NGOs to continue leprosy • Tools to measure the impact of MDT interven- research. Of course, it may not be possible for WHO tion on the disease incidence. to address all the research issues on leprosy. Other • HIV and leprosy. groups and academics will continue to follow their • Simulation modelling. own research agendas for various reasons (funding,

70 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 71 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 approaches 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 countries, 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 community 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 participation of national programme managers, elimination programmes at all levels, and the research community.

70 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 71 72 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 73 Annex 8a Latest information on the leprosy situation at country level by WHO region

72 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 73 Leprosy Situation in Africa*

Country Point Cases Prevalence Detection Prevalence detected per 10 000 per 100 000 during the year 2001 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

74 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 75 Leprosy Situation in the Americas Country Point Cases Prevalence Detection Prevalence detected per 10 000 per 100 000 during the year 2001 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 the Eastern Mediterranean Region Country Point Cases Prevalence Detection Prevalence detected per 10 000 per 100 000 during the year 2001 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 South-East Asia Country Point Cases Prevalence Detection Prevalence detected per 10 000 per during the 10 000 year 2001 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

74 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 75 Leprosy Situation in the Western Pacific 2001

Country Point Cases Prevalence Detection Prevalence detected per 10 000 per 100 000 during the year 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 58 88 4.8 72.7 Micronesia 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

76 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 77 Geographic distribution of leprosy in 2002: prevalence per 10 000 population 2 to 5.3 (4) 1 to 2 (6) 0 to 1 (73) Geographic distribution of leprosy in 2002: per prevalence 10 000 population

76 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 77 78 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 79 Annex 9 WORKING PAPER: Issues related to the intensity of Mycobacterium leprae transmission

78 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 79 ISSUES RELATED TO and by defaulting and relapse cases, and is heavi- THE INTENSITY OF ly influenced by the intensity of case-finding efforts. Trends in the CDR may thus be distorted as a result MYCOBACTERIUM LEPRAE of bias and confounding. The implications of BCG TRANSMISSION vaccination, cross-immunization or competing risk by tuberculosis, increased natural immunity, and Paul R. Klatser the HIV pandemic on leprosy incidence, can only KIT Biomedical Research, Koninklijk Instituut voor be guessed at. CDR trends are, on a global scale, rel- de Tropen/Royal Tropical Institute (KIT), Amsterdam, atively stable, while at country level CDRs show a The Netherlands. declining, stable or even rising trend.

INTRODUCTION Because the causative organism of leprosy, Mycobacterium leprae, cannot be cultured in vitro, it The current strategy for eliminating leprosy is based is virtually impossible to assess exposure and the on the presumption that, once the prevalence is onset of infection and disease. As a consequence, below 1/10 000 at global level, transmission will the chain of infection, considered as the relationship dwindle and eventually stop (1). This assumption between M. leprae, transmission and the human is likely based on the fact that MDT affects the pool host, is poorly understood. of infectious patients, but the question as to whether it affects this pool sufficiently is not yet answered. Several studies on the epidemiology of leprosy do The major challenge for the leprosy research com- however allow us to make at least some inferences munity in the near future will therefore be to pro- about the properties of M. leprae, its host, and the vide evidence that the current strategy of leprosy contact patterns between these two, factors that, in elimination is feasible, and functions according to concert, determine the ability of leprosy to spread. expectations. THE PATHOGEN Using registered prevalence as a proxy indicator for the epidemiology of leprosy has several caveats (2). Although M. leprae cannot be cultured in the lab- By definition it only reflects registered cases, and oratory, and thus cannot be used to meet Koch’s thus obscures the existence of true leprosy patients postulates, few people doubt that M. leprae is the not reported to the health facilities and of default- cause of infection which leads to leprosy. M. leprae ers who are continuously removed from the regis- is an obligate intracellular bacterium in the order ters. Inconsistencies in case definition and diagnosis Actinomycetales. It measures 0.3-0.5 x 4.0-7.0 µm due to changed diagnostic criteria make compari- and its optimal growth temperature has been deter- son of prevalence rates over the years and between mined to be 30°C. In mice it divides only once in 12 programmes difficult if not impossible. The preva- to 14 days, and the bacteria may remain viable for lence used in leprosy control is the point prevalence several days outside the body. Until recently, i.e. (taken at a certain moment in time) and not the peri- until the genome sequence became available, most od prevalence. This rate is affected by the duration studies on the genetic composition of distinct M. lep- of the disease, the more so because patients with a rae isolates failed to yield evidence for the existence short treatment of less than one year may not be of different strains of M. leprae. included (at present PB patients; in future maybe also MB patients). Taking the influence of these fac- The high rate of self healing among persons present- tors on prevalence into account, it is clear that MDT ing with early monomacular lesions suggests that has had a major impact on prevalence of the disease M. leprae is a poor pathogen. The presence of specif- and will continue to do so in the near future pro- ic immune responses to M. leprae in healthy subjects vided that access to care is sustained at the current indirectly suggests that the presence of M. leprae in a level. human is not associated with disease per se. Whether widespread infection is as common as often thought Incidence would, in principle, be a better measure is questionable. The early indirect proof for this for monitoring the trends in transmission, but vir- was based on in vitro assays of lymphocyte trans- tually no information on incidence rates exists (3,4) formation in the presence of M. leprae antigens (5), nor is it likely to become available considering the but these assays were not specific and were liable difficulties associated with measuring it. Case detec- to confounding. The presence of antibodies to PGL- tion rates (CDR) are available for leprosy, but are far I is probably specific, but good quality testing often from good indicators of incidence, let alone trans- indicates only a relatively low percentage of posi- mission. The CDR may be inflated by backlog cases tives (up to 5%) among very high risk groups such

80 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 81 as household contacts of multibacillary patients (6). CONTACT PATTERNS Transient nasal carriage of M. leprae in the healthy It is often thought that most cases of leprosy arise population, as evidenced by PCR, is not likely to from the non-contact population, similar to tuber- reflect infection but rather environmental contami- culosis, where casual contact plays a significant role nation (7). On the basis of these studies, it is often in transmission. However, the long incubation time concluded that M. leprae infection is far more com- in leprosy makes it difficult to obtain contact his- mon than believed, thus implicating casual contact tories. There are now several studies which clearly as a major factor in transmission, as in tuberculosis. show that close contact is more important than often However, this author is of the opinion that there is believed (12,13). The risk of developing leprosy is little evidence for widespread M. leprae infection. greatest among close contacts of leprosy patients, like household contacts, but also neighbours and Multibacillary leprosy patients are thought to be a social contacts, and particularly close contacts of main source of infection, being able to shed large multibacillary patients – the attack rate among per- numbers of bacteria from the nose – on average, 107 sons living in the household of a multibacillary viable M. leprae per day (8). It is very likely that these patient can be five to ten times as high as among patients have already been contagious for a consid- non-contacts. Household contacts of paucibacil- erable length of time before the definite diagnosis. lary patients experience a two-fold risk of develop- Disability at the time of registration is a well known ing leprosy disease compared to non-contacts. These and common phenomenon illustrating the delay findings are a sign that the likelihood of disease var- in patient detection (9). Early lepromatous leprosy ies with the degree of contact and with the intensity is often difficult to diagnose because patients may of the infectious source. However, exposure of both present no lesions and no definite loss of sensation. the index case and close contacts to a common environmental source of infection is theoretically possi- If indeed the nose is the port of exit for M. leprae ble as well. bacteria, transmission is likely mediated by droplet spread. In contrast to airborne spread through The view that patients are the single source of infec- coughing, as in the case of tuberculosis, droplet tion is possibly too narrow. In any case, it is well spread requires close proximity/contact with the conceivable that multibacillary leprosy patients, and host since droplets (defined by a size >5 µm) do not paucibacillary patients to a lesser extent, are infec- spread more than 1 metre. Such a mode of transmis- tious long before their clinical diagnosis, since the sion would well fit the observed contact patterns majority of new cases are only diagnosed years after (see below). the onset of disease. This group of patients may pose a serious threat to the control of transmission Apart from being a portal of exit, it is also likely of leprosy, which is mainly based on case finding. that the nose is a portal of entry for the bacteria; this It was previously shown, using the enzyme linked entry may be facilitated by small injuries in the nasal immunosorbent assay (ELISA), that seropositive mucosa (10). Experimental transmission of leprosy contacts of leprosy patients have a relative hazard in nude mice has been demonstrated through nasal of 8 for developing leprosy, and of 25 for developing inhalation, and was most successful when the nasal MB leprosy, compared to seronegative contacts (14). tissue had been lightly abraded. It might be worth- These results clearly show that serology can be used while further exploring the role and condition of as a tool to identify contacts of leprosy patients with the nasal mucosa in transmission of, and suscepti- a high risk of developing leprosy. Screening contacts bility to, leprosy. Impairment of nasal function may of leprosy patients in order to find and follow-up or enhance the development of disease, as is seen in treat those at increased risk of developing the dis- other infectious diseases (11). ease may ultimately prevent transmission. The skin has also been considered to be a possible The rarity of secondary cases among contacts of port of exit and entry of leprosy bacteria, most likely immigrant leprosy patients in non-endemic coun- due the prominent role it plays in disease manifes- tries remains puzzling. It could mean that host and/ tation. Untreated lepromatous patients are likely to or environment related factors play a prominent role be able to shed large numbers of bacteria from their in the transition from infection to disease. Some fac- ulcers or otherwise injured skin. However, since tors in the chain of contact and transmission (e.g. there is no evidence that M. leprae can penetrate closeness of contact, skin contact, impairment of intact skin, only accidental inoculation with M. lep- nasal integrity by typical concomitant respiratory rae would favour the skin as a possible port of entry. infections) may be specific to areas of current ende- Evidence for a possible role of arthropods in trans- micity. mission of leprosy is circumstantial at best (11).

80 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 81 PROPERTIES OF THE HOST culosis have been documented since the mid-1980s. There has been much speculation on the possible The immune status of the host has been implicated epidemiological impact of HIV on the leprosy sit- as an important factor in the process leading from uation. Several studies have reported conflicting infection to disease and, to a lesser extent, in trans- results, but globally there is no indication that the mission itself (since we cannot measure infection). HIV epidemic is leading to a significant increase in The environment can both undermine (through the number of leprosy patients. The impact of HIV malnourishment, recurrent infections, HIV infec- may be minimal because it simply takes too much tion) and boost (through BCG vaccination) the time for symptoms to develop from an infection immune system, while innate resistance is deter- with M. leprae (11). 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 exposure 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 susceptibility to leprosy per se was produced in several 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 certain ‘high risk’ histocompatibility leukocyte antigen (HLA) type still have a very low risk (generally less than 1%) of developing leprosy or a particular type of leprosy. Environmental and behavioural factors may be of such importance that they obscure genetic involvement. Evidently, genetic predisposi- tion is only one factor in the complex process leading 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 socioeconomic 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 leprosy, although studies have shown the degree of protection to vary from 20% to 80% (15). BCG immunization 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-

82 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 83 References 15. Fine PEM. BCG vaccination against tuberculosis and leprosy. British Medical Journal, 1988, 44: 691-703. 1. Leprosy. Fact sheet no. 101. Geneva, World Health Organization, January 2001. 16. Chaudhury S et al. An eight-year field trial on anti- leprosy vaccines among high-risk household contacts in 2. Visschedijk J et al. Mycobacterium leprae – millennium Calcutta metropolis. International Journal of Leprosy, resistant! Leprosy control on the threshold of a new era. 1994, 62:389-394. 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 population 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 disability 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 epidemiology 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: implications 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 household contacts. Submitted for publication, 2003.

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Leprosy

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Annex 10 WORKING PAPER: Vaccines for leprosy and other mycobacterial diseases – what do we know today? Leprosy

84 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 85 VACCINES FOR LEPROSY In a prospective study in South India (Chingleput), AND OTHER MYCOBACTERIAL in which the efficacy of BCG against tuberculosis and leprosy was studied, BCG was found to give limited DISEASES – WHAT DO WE overall protection against leprosy (17% and 24% for KNOW TODAY? two different doses), but no protection against smear positive forms of the disease (Table 1) (2). M.D. Gupte, P. Manickam, B. Kishore Kumar National Institute of Epidemiology (Indian Council MULTI-ARM LEPROSY VACCINE of Medical Research), Chennai – 31, India. TRIAL IN SOUTH INDIA During 1991-1998, a concurrent comparison of four INTRODUCTION candidate vaccines, namely BCG, BCG + HKML, M. w, and ICRC, was undertaken in a vaccine trial Vaccines are considered for use against some of the in South India (5). The protective efficacy of BCG + mycobacterial diseases, viz. tuberculosis, leprosy HKML and ICRC was in the order of 65% at the sec- and Buruli ulcer (1). BCG happens to be the vaccine ond follow-up survey, 4-8 years after vaccination that has been considered for use in all three condi- (Fig. 1). In the Jordan report (6) of the US National tions, although several other vaccines – first genera- Institutes of Health, these findings were considered tion vaccines – have also been tried against leprosy: very important, and further analysis and testing of • Tuberculosis (TB): BCG the ICRC and BCG + HKML candidate vaccines was • Buruli ulcer: BCG suggested. • Leprosy: BCG, BCG + killed Mycobacterium leprae, ICRC, M. w, M. habana In the trial, about 11% of vaccinated subjects had received prior BCG vaccination. Sub-group analy- FIELD TRIALS OF BCG FOR LEPROSY sis of subjects who had received prior BCG vaccination compared with subjects who had not received The efficacy of BCG against leprosy has been inves- prior BCG vaccination was carried out. The efficacy tigated in several parts of the world (1,2). In trials of the various vaccines was similar in both BCG scar conducted in India and Malawi (3), the protective positive and negative groups (unpublished). Vaccine efficacy of BCG against leprosy was found to be bet- efficacy for different age groups indicated that the ter than against tuberculosis, although there was vaccines were effective even in previously infected wide variation in the estimates of protective effica- individuals. The third follow-up survey of the vac- cy against leprosy. Trials in Venezuela and Malawi cine trial is nearly completed and the results will be (4) yielded very similar conclusions: BCG was effec- available by March 2003. So far in the third follow-up tive, and repeated doses of BCG conferred addi- survey, there are about 120 new (provisional) cases tional protection, but the addition of heat-killed M. in the vaccinated cohort, compared to over 600 and leprae (HKML) did not offer any additional benefit. 300 cases in the first and second follow-up surveys The protection offered by BCG was again higher for respectively, indicating possible overall reduction of leprosy than tuberculosis. leprosy in the cohort population (unpublished).

Table 1. Incidence of leprosy 0.1 mg BCG* 0.01 mg BCG* Placebo P value and protective efficacy of BCG Number of new cases 3213 3497 4238 by dose in a leprosy prevention Incidence rate per 1000 6.6 7.2 8.8 < 0.001 trial in Chingleput, South India Protective efficacy % 24.4 17.4 ( 20.9, 27.8 ) (-21.0, 13.6) Number of smear positive new cases 40 39 42 Incidence rate per 1000 0.082 0.081 0.087 0.8 Protective efficacy % 5.1 7.1 ( - 46.3, 38.5 ) ( -43.7, 39.9)

* Numbers in parentheses are 95% confidence intervals

86 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 87 MODEL PREDICTIONS ISSUES FOR VACCINE TRIALS Our recent work with a simulation model for lepro- IN THE FUTURE sy predicted that the introduction of a vaccine with Presently several new vaccines are being developed 65% protective efficacy against leprosy could bring against tuberculosis, and new information is becom- about a dramatic decline of leprosy incidence (7). ing available for both M. tuberculosis and M. leprae. Perhaps the only way to expect new developments BCG AND TUBERCULOSIS in leprosy vaccines is to link efforts with tuberculosis in developing newer vaccines. BCG is known to work against tuberculosis by preventing primary infection. How it works against the The main issues to be addressed in designing new other diseases is not clear. vaccine trials for mycobacterial diseases include the incidence of disease, sensitivity and specificity of Ginsberg commented in a recent article (8) that BCG diagnostic tools, availability of surrogate markers, was developed as a vaccine against TB in the first possible negative effect of the vaccine, operational two decades of the 20th century, but still, 70 years difficulties, and ethical issues (3,11). later, it is the only available vaccine against TB. Several trials have been conducted worldwide to Low incidence of the disease would have implica- evaluate the efficacy of BCG in protecting against tions for sample size, and subjects would have to be tuberculosis; results have shown this to vary from followed up for a longer period. The magnitude of 0% to approximately 80% (1,9,10). confounding of the vaccine efficacy estimates would depend on diagnostic validity in the field situation. Fine et al (1) have reviewed the findings related to the Another serious and controversial issue is that of a protective efficacy of BCG for tuberculosis and lepro- negative effect of the vaccine, which is clearer when sy; the summary information is reproduced in Fig. 2. 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 ��

86 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 87 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � CT = clinical trial trial CT = clinical study CC = control case = COH cohort study contact study HH = household � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � | � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � ** Studies of pulmonary disease in children of pulmonary disease ** Studies � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � (1) (1) | � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � Fine PEM et al., 1999 Fine PEM et 1999 al., � � � � � � � � � � � � � � � � � � Source: Source: � * * Figure 2. Estimates of BCG efficacy against different forms of tuberculosis and leprosy from observational and experimental studies conducted worldwide*

88 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 Report of the Scientific Working Group on Leprosy, 2002 • TDR/SWG/02 89 References 7. Gupte MD et al. Modeling epidemiology of Leprosy. Indian Journal of Leprosy, 2000, 72(3):305-315. 1. Fine PEM et al. Issues relating to the use of BCG in immunization programmes: discussion document. Geneva, 8. Ginsberg AM. What is new in tuberculosis vaccines? World Health Organization, Department of Vaccines and Bulletin of the World Health Organization, 2002, 80(6): Biologicals, 1999. 483-488.

2. Gupte MD. Field trials of anti-leprosy vaccines [editori- 9. Colidtz GA et al. Efficacy of BCG vaccine in the preven- al]. Indian Journal of Leprosy, 1998, 70(4):363-367. tion of tuberculosis. Meta-analysis of the published literature. Journal of the American Medical Association, 1994, 3. Gupte MD. Field trial of leprosy vaccines. In: Raghunath 271:698-702. D, Nayak R, eds. Trends in malaria and vaccine research: the current Indian scenario. New Delhi, Tata McGraw-Hill, 10. Colidtz GA et al. The efficacy of bacillus Calmette- 2002:250-259. Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published 4. Gupte MD. Vaccine trials in leprosy – Venezuela, literature. Pediatrics, 1995, 96:29-35. Malawi and India. International Journal of Leprosy, 1999, 67(Suppl):S32-S37. 11. Gupte MD, Sampath DK. Ethical issues considered in Tamilnadu leprosy vaccine trial. Issues in Medical Ethics, 5. Gupte MD et al. Comparative leprosy vaccine trial 2000,VIII(1):10-12. in South India. Indian Journal of Leprosy, 1998, 70(4): 369-388. 12. Gupte MD. South India immunoprophylaxis trial against leprosy: relevance of the findings in the context of 6. Accelerated development of vaccines. USA, National trends in leprosy. Workshop proceedings. Leprosy Review, Institutes of Health, Jordan Report, 2000:26. 2000, 71(Suppl.):S43-S49.

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