Research Priorities for Leprosy and Current Opportunities

C. W. Smith

Two major reviews of research priorities for leprosy were done in 2002 and 2003. A major systematic review of the leprosy literature was conducted in preparation for the International Leprosy Association Forum prior to the 2002 International Leprosy Congress in Brazil. The ILA Forum report (1) was published in the major leprosy journals and included recommendations for research. The WHO/TDR programme also held a Scientific Working Group on Leprosy, which identified priorities for leprosy research documented in a report published in 2003 (2). Both reports produced very similar recommendations on transmission, nerve function impairment and implementation of leprosy control services. This included research to improve understanding of transmission, infection and the development of disease, the need to develop tests for M. leprae infection and disease, develop chemoprophylaxis for high risk individuals, shorter uniform Multidrug therapy (MDT), and methods of surveillance for rifampicin resistance in relapsed cases. Research was recommended to improve identification of patients at risk of nerve function impairment, and improved prevention and treatment of nerve damage. Implementation and operational research was recommended to improve the coverage and quality of leprosy control, prevention of disability and rehabilitation within integrated health settings.

Review of the research conducted since 2002 shows that many of these recommendations have been addressed, but there are some outstanding. The WHO Global Strategy for Further Reducing the Leprosy Burden and Sustaining Leprosy Control Activities (2006-2010) published in 2005 (3) highlighted the 4 key research priorities as follows:

  1. Prevention and management of nerve function impairment and reactions
  2. Improved Chemotherapy
  3. Developing and improving of diagnostics to identify individuals at high risk of developing leprosy, understanding transmission and host responses
  4. Operational Research to improve sustainability and integration of leprosy services
Current Research Opportunities to Address on the Priorities for Research
  1. Prevention and management of nerve function impairment and reactions
  2. In June 2007, an International Workshop on Neuropathy in Leprosy was held in the Netherlands. The main topics discussed were mechanisms of neuropathy in leprosy, screening and diagnostic testing of nerve function, and treatment of neuropathy in leprosy.

    The objective of the workshop was to bring together and discuss evidence, develop consensus, and set an agenda for future research and action regarding neurological aspects in leprosy. A Consensus Report of the meeting will be published in Leprosy Review (4).

    Trials of prophylactic steroids have demonstrated a short-term effect on prevention nerve function impairment but further work is needed to develop the optimal regimen. Trials of steroid and non-steroid treatment regimens have also been conducted. New markers (e.g. nerve conduction and temperature sensation) to identify high-risk patients have recently been demonstrated. The research potential is in combining use of markers of high risk with improved prevention and treatment regimens, and this will require new funding.

  3. Improved Chemotherapy
  4. A multi-centre trial of a uniform regimen of multidrug therapy is currently being conducted in India and China, funded by WHO and TDR. The uniform regimen is the based on the current MDT regimen given to MB leprosy patients and includes rifampicin, dapsone and clofazimine, given for a 6-month period to all types of leprosy patients (5). Such a regimen would greatly facilitate integrated programme logistics in terms of drug delivery and the remove the need to classify leprosy for treatment purposes. The problem of possible rifampicin resistance has recently been discussed during a WHO workshop at the JALMA Institute in Hyderabad, India, where evidence was presented of secondary and primary resistance of M. leprae to this crucial antileprosy drug (6). The surveillance of rifampicin resistance using genetic methods is currently being established.

  5. Developing and improving of diagnostics to identify individuals at high risk of developing leprosy, understanding transmission and host responses
  6. Following the WHO/TDR recommendations from 2003 regarding research priorities in the area of new diagnostic tests and molecular tools, a large research consortium was started under the name IDEAL (Initiative for Diagnostic and Epidemiological Assays for Leprosy).

    IDEAL aims at improving diagnosis of M. leprae infection and pre-clinical leprosy through the development of a new generation of diagnostic assays that are based on recent knowledge of the genome of M. leprae and other (myco)bacterial genomes (7). The combination of a better understanding of the epidemiology and transmission of leprosy through molecular typing of M. leprae will enable testing of tailor-made intervention(s) aimed at the prevention of leprosy. The IDEAL programme thus focuses on the development of immunology-based diagnostic assays for early diagnosis and the development of assays for molecular epidemiology for transmission studies. Emphasis of the research activities is on the identification of new target antigens for cellular and humoral assays that are applicable in endemic areas with genetically diverse backgrounds, and the identification of short tandem repeats (VNTRs) that are suitable for studying transmission of M. leprae. The newly developed tests urgently need to be field tested to assess their validity and reliability. The unravelling of the genome of M. leprae has contributed to the phylogenetic tracing of worldwide dissemination of leprosy and the development of typing systems (9). Important advancements have also been made in the area of genetic susceptibility. Recent evidence suggests a strong host-genetic component to susceptibility to leprosy infection (10). Funding is required to implement this research.

  7. Operational Research to improve sustainability and integration of leprosy services
  8. In the past 25 years leprosy case detection has been determined in many countries by operational factors such as expanding of control activities during the elimination drive leading up to 2000 and decreased activities afterwards. Operational influence is particularly visible in India, where new case detection dropped by 75% from 559,938 in 2000 to 139,252 in 2006 (8). At the same time the proportion of new cases with WHO grade 2 disability increased by 38% between 2004 and 2007, from 1.6% to 2.2%. This increase suggests less active case finding. Such dramatic drops within a short period of time are not credible biologically because of the long incubation period of leprosy and the absence of an instantaneously implemented high coverage preventive intervention such as vaccination in the decade preceding the sudden drop in case detection. The current sharp fall in new case detection rates is therefore most likely to be due to failure of the integrated programme to detect cases.

    This endorses the importance of operational research to improve the sustainability of all aspects of the leprosy services detection, treatment, prevention of disability and rehabilitation.

References
  1. ILA Technical Forum. Report of the International Leprosy Association Technical Forum. Int J Lepr 2002; 70 (supplement):S1-62.
  2. World Health Organisation/Tropical Disease Research Programme. Report of TDR Scientific Working Group.
  3. World Health Organisation. Global strategy for further reducing the leprosy burden and sustaining leprosy control activities (2006-2010) World Health Organisation, Geneva, 2005.
  4. W.H. van Brakel, et al. International Workshop on Neuropathy in Leprosy Consensus Report. Lepr Rev (in press)
  5. World Health Organisation. Report of the Seventh Meeting of the WHO Technical Advisory Group on the Elimination of Leprosy, Geneva, 4-5 April 2005.
  6. World Health Organisation. Rifampicin Resistance in Leprosy. Report of an Informal Consultation. National JALMA Institute of Leprosy and other Mycobacterial Diseases, Agra, India, 30 November 1 December, 2006.
  7. Aseffa A, Brennan P, Dockrell H, Gillis T, Hussain R, Oskam L, Richardus JH, (2005). Report of the First Meeting of the IDEAL (Initiative for Diagnostic and Epidemiological Assays for Leprosy) consortium held at Armauer Hansen Research Institute, ALERT, Addis Ababa, Ethiopia on 24-27 October 2004. Lepr. Rev., 76:147159.
  8. Anonymous. Global leprosy situation, 2007. Wkly Epidemiol Rec 2007; 82: 225-32.
  9. Monot M, Honore N, Garnier T, Araoz R, Coppee JY, Lacroix C, et al. On the origin of leprosy. Science (New York, NY. 2005 May 13;308(5724):1040-2.
  10. Alcais A, Alter A, Antoni G, Orlova M, Nguyen VT, Singh M, et al. Stepwise replication identifies a low-producing lymphotoxin-alpha allele as a major risk factor for early-onset leprosy. Nature genetics. 2007 Apr;39(4):517-22.