Global Leprosy-Leprosy Research Support-Colorado State University

Leprosy As It Was The 1st International Leprosy Congress was held in Berlin in 1897, and the only points on which all experts agreed was that leprosy was incurable, and that the only immediate solution was to isolate patients. The first formal attempt to estimate the global leprosy burden was made by WHO in 1966, resulting in an estimated total number of cases of 10,786,000, 60% of whom were not registered for treatment. This figure was updated in 1972, giving a lesser estimate of 10,407,200 cases. The WHO Expert Committee, in its fifth report, estimated a figure of over 12 million cases, and the WHO Study Group on the Epidemiology of Leprosy in Relation to Control, in 1983, referred to an estimate of 11,525,000 cases. An estimated figure of 10-12 million was frequently mentioned in many documents in the mid-1980s. It was obvious by the mid-1970s that the efforts to control leprosy by long-continued, even life-long, dapsone monotherapy were failing, leading to the establishment of WHO/TDR of research programs directed at development of an effective protective vaccine (IMMLEP) and of more effective therapy (THELEP). History shows that THELEP was the clear winner, but the recent evidence of the success of the only WHO vaccine at the time (heat-killed M. leprae plus live BCG) in the Tamilnadu, South India trial [as against its failure in Mali and Venezuela provides some hope. The exact extent of dapsone-resistant M. leprae among patients with multibacillary leprosy has long been debated. Nevertheless, multiple surveys showed that both secondary and primary resistance to dapsone were widespread, with the prevalence of secondary resistance ranging from 10 to 386 per 1,000, and that for primary resistance as high as 550 per 1,000. On the other hand, by analogy with tuberculosis, it was believed that treatment by regimens composed of two or more drugs, each acting by a different antimicrobial mechanism, would prevent relapse with dapsone-resistant M. leprae. In particular, the rapid bactericidal action of rifampicin raised hopes that treatment with this drug would prove curative. A major line of investigation at the time comprised controlled clinical trials among patients with lepromatous leprosy, to examine the efficacy of various combined-drug regimens in reducing the proportions of patients harboring persisters, or the numbers of persisting M. leprae harbored by patients. In particular, follow-up of MB patients whose treatment had been deliberately terminated when they were still smear-positive suggested that the risk of relapse of MB leprosy after termination of chemotherapy, especially with 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, once treatment had been terminated. Because of its extraordinarily potent bactericidal activity against M. leprae, rifampicin became an essential component of regimens, and dapsone and clofazimine were included to prevent the emergence of rifampicin-resistant M. leprae. Shortly thereafter, the WHO Leprosy Unit convened the Study Group on Chemotherapy for Leprosy Control. The Study Group recommended combined-drug regimens based upon the supervised intermittent administration of rifampicin for both MB and paucibacillary (PB) leprosy. These WHO "Study-Group regimens" were then widely applied in programs of leprosy-control and, as we now know, are very effective, well tolerated, and are well accepted by both patients and medical staff.

	Leprosy Today Due to the substantial progress in leprosy control through MDT, the World Health Assembly (WHA) in 1991 was prompted to call for the "elimination 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. The figures and trends at the time suggested that this ambitious goal could be achieved. Based on available information and its interpretation, global estimates had dropped from 10-12 million in 1985 to 5.3 million in 1991. At that time also, the large number of patients who had been cured and discharged from the registers but who still had residual Grade 2 deformities were estimated at 2-3 million. The so-called Leprosy Elimination Project had the effect of galvanizing governments, non-government funding agencies (such as those of ILEP), and communities, and, in the subsequent years, the WHO LEAG developed the concept of LECs (Leprosy Elimination Campaigns), and SAPELs (Special Action Programs for the Elimination of Leprosy), with the purpose of detecting and treating all patients, including those in "unreachable" geographic areas. The result was that, in 1996, the prevalence was 926,259 (a rate per 10,000 of 1.67), and in 1997, the prevalence was 888,340, (1.54 per 10,000), with an estimated number of cases of 1.15 million. In 1998, the prevalence was 828,803, with a rate of 1.39 per 10,000, still short of the goal of the World Health Assembly. In the meantime, there was a steady increase in the number of new cases reported. For example, if one examines the leprosy trends in the top 32 endemic countries rather than globally, one sees that, while the prevalence dropped dramatically from 3.997 million (21.1 per 10,000) in 1985 to 768,619 (3.2 per 10,000) in 1997, the new case detection was 550,224 (29 per 10,000) in 1985, 550,743 in 1989; 667,133 in 1992; 553,768 in 1994; 673,893 in 1997. In 1998, the number of new cases detected in the 55 countries reporting to WHO was 714,876. At the beginning of 1999, out of 122 countries which were considered endemic in 1995, 94 had reached the elimination target, and the leprosy prevalence had been reduced 85% since 1985. Thus the figures for global prevalence was 834,988 registered cases with a 1.4 rate per 10,000, excellent, but well short of the WHA goal. However, the numbers of new cases detected continued to increase; the number at the beginning of 1999 was 795,117 (13.3 per 100,000). WHO/LEAG attributed 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-registration of previously treated cases (about 50% of the cases are attributed to the widescale introduction of the LECs).

The Continuing Need for Leprosy Research and Central Resources

Although the reduction in prevalence is dramatic in historical terms, there is clearly a distinct drop-off in the reduction curve. Moreover, even the global prevalence rate of 1.4 per 10.000 is far short of the WHA goal, and, in the top 13 countries, it is unreachable in the short-term (e.g., 5.9 in India, 4.3 in Brazil). Thus, the present elimination approach is apparently inappropriate for these countries, perhaps reflecting the limitations of the MDT technology itself, and WHO, in conjunction with the national programs, are undertaking a country-by-country reassessment. However, nowadays there is an element of desperation within the research ranks because epidemiological research on new drug development and diagnosis has largely disappeared. In particular, diagnosis over the last ten years, and particularly within the LECs of today, has been simplified to mere physical examination.

Secondly, there is the issue of "incidence." It is very difficult today to understand the current trends in leprosy incidence. There are a number of reasons for this, which have been extensively explored by P. Feenstra, P. G. Smith, and recently by W. Cairns Smith. He reasons that it is very difficult to calculate accurately incidence rates when these are very low and to estimate secular infection in the community and a reduction in transmission of infection has face validity. However, the infectivity of patients prior to detection and treatment, the possibility of asymptomatic carriage, environmental reservoirs, and the clustering of cases in the community, challenge this assumption. Indeed, further evidence for environmental reservoirs of M. leprae has emerged from recent, unpublished work by S. Izumi et al., to add to the overpowering evidence that the possum and the badger are reservoirs for M. bovis in New Zealand and England/Ireland, respectively, and there is more and more evidence for nasal carriage of M. leprae. If the current elimination strategy is to have an effect on transmission, it is unlikely to be obvious immediately because of the long incubation periods. Mathematical modeling suggests that the declined incidence rates are likely to be rather gradual, and in the order of halving every 30-40 years. Many factors other than MDT influence incidence rates, including BCG immunization, socio-economic improvement and reduced overcrowding. Dr. Smith recommends, firstly, sustaining the reduction in prevalence by ensuring effective case detection and treatment of all new cases. Secondly, he recommends a return to research.

Prevention of disability is seen by many to be the ultimate goal of leprosy control and therefore needs to be part of any credible strategy. Indeed, innovative treatments have emerged from Kaplan et al. Over recent years, there have been major steps taken to simplify the prevention of disability for integrated programs, and these new strategies need to be taken on board. Similarly, linking with rehabilitation agencies is also important.

In 1994, on the heels of the WHA declaration, P. Feenstra said, "Reduced prevalence does not necessarily reflect a decline in incidence, and we do not yet have convincing evidence that MDT has an impact on the incidence of leprosy," and "The problem of leprosy and leprosy-related disability will continue to exist far beyond the turn of the century." How true he was!

Dr. D. B. Young has best summarized the needs and challenges: "It is important that priorities are set for leprosy research which will support the leprosy elimination program. These would include the development of tests for leprosy exposure (both skin tests and simple blood tests), tests for the prediction of reactions, and better means of prevention of nerve damage. In the long term, research could provide tools for surveillance of transmission, reactivation of disease, detection of non-human sources of infection, and emergence of drug-resistant leprosy strains. Active preventative interventions such as chemoprophylaxis or vaccination of 'at risk' groups, identified by further research, would further reduce the incidence of leprosy. The lessons learned from leprosy will not only benefit the patients, but provide further insights into the basic processes of bacterial genetics, neurobiology, and immunology."