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Chemotherapy And Chemoprophylaxis Of Leprosy

17 Jan 2008

Source: WHO/TDR

Baohong Ji

Bactériologie et Hygiène, Faculté de Médecine Pitié-Salpêtrière, Paris, France

Working paper for the Scientific Working Group meeting on Leprosy Research, convened by the Special Programme for Research and Training in Tropical Diseases, Geneva, 26–28 February 2002

Full text source: Scientific Working Group, Report on Leprosy, 26–28 November 2002, Geneva, Switzerland, Copyright © World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases, 2003, http://www.who.int/tdr/publications/publications/swg_leprosy.htm

Chemotherapy

Newer Generation MDT Regimens

After 2005, a new target date for global elimination of leprosy will exist, and new patients will continue to emerge, but control programmes may be significantly weaker. Under this very complicated situation, newer chemotherapeutic regimens that are more effective and operationally less demanding are required [1]. To develop newer generation MDT regimens, powerful bactericidal drugs against M. leprae are needed. Previous experience [2] demonstrated that screening of existing compounds is the only cost-effective way to develop drugs for leprosy, and should be encouraged. The most productive approach is to screen compounds that display powerful activity against either a wide spectrum of gram-positive microorganisms in general or cultivable mycobacterium in particular, or that exhibit pharmacokinetic properties more favourable than those exhibited by the member of the class presently employed for treatment of leprosy [3].

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

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

A Common Regimen for PB and MB Leprosy

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

It is not necessary to include PB patients in the trial.
The definition of MB leprosy [10] is too broad and includes many cases who are in fact PB leprosy from the bacteriological and chemotherapeutic points of view [11].
The definition of relapse [10] is too vague and it will be difficult to distinguish relapse from leprosy reactions. More important is that, because skin-smear examination, one of the key indicators for diagnosing MB relapse [12,13], is not employed, the quality of diagnosing MB relapse will be compromised.
Patients should be followed up more than five years after stopping treatment, otherwise only part of the relapse will be detected.

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

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

Drug Resistance

Emergence of rifampicin resistance would create tremendous difficulty for the treatment of individual patients, and its widespread dissemination would pose a serious threat to achieving the final goal of leprosy control. Previous experience [18] indicates that rifampicin resistance could emerge rather rapidly in a non-negligible proportion of patients whose treatment regimens were inappropriate. Although more than 10 million leprosy patients in the world have completed treatment with MDT, and rifampicin-resistant leprosy has not been reported among these patients [7,17], one must be cautious in interpreting the findings, because:

post-MDT surveillance for relapse has been discontinued
during the last decade, rifampicin-susceptibility testing has rarely been carried out, and the results are not always dependable.

Therefore, the current situation regarding rifampicin-resistant leprosy in unclear. Before the problem becomes so frequent that it threatens leprosy control, solid information about its magnitude should be collected from different part of the world.

Due to administrative, financial and technical reasons, it is no longer feasible to undertake a relatively large-scale survey of rifampicin-resistant leprosy by mouse footpad technique. On the other hand, because the available results of polymerase chain reaction (PCR)-based DNA sequence analysis of the rpoB gene of M. leprae were in full concordance with those of the susceptibility testing carried out in the mouse footpad system [19–22], the method could be applied as a cost-effective alternative technique for monitoring rifampicin-resistant leprosy. Although more studies on the association between rifampicin resistance and rpoB mutation, particularly at positions other than Ser531 or His526, should be pursued, it is reasonable to conclude that, based on identification of rpoB mutation with amino acid substitution of Ser531 or His526, this approach may lead to the diagnosis of a good 80% of rifampicin-resistant strains of M. leprae [22,23].

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

Recently there have been reports of multidrug-resistant M. leprae [22,24–26]. Besides resistance to rifampicin, the strains were also resistant to at least one more drug other than dapsone, including ofloxacin [22,23,26] and sparfloxacin [25]. Although the number of multidrug-resistant strains remains small, their occurrence is indeed an alarm bell and must be closely scrutinized.

Accompanied MDT

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

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

However, to accelerate the leprosy elimination process, recently the WHO leprosy programme and its TAG have changed dramatically their position on supervised therapy. They concluded that, after the first dose of MDT, “supervision of the subsequent monthly component of MDT regimens is no longer essential” [9]. Further, based on this conclusion, they recommended large-scale implementation of accompanied MDT (AMDT) [9], which refers to a policy that patients are provided the entire supply of MDT drugs - six months of medication for a PB case and 12 months for a MB case - at the time of diagnosis, while choosing someone close to them to accompany them with their treatment [16,17]. Some members of TAG even believe that monthly supervision “hampers integration and is not user-friendly”, and that “providing patients with a full course of treatment on their first visit is both patient- and staff-friendly and will improve compliance” [9].

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

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

Whether AMDT is to be applied as a routine or only in special situations
Who may be chosen to supervise the patient's treatment - health workers, community volunteers, or family members of the patients? What is the order of preference? In TB, opinions differ regarding supervision by family members, which is common in DOT programmes; most workers believe that supervision by family members is less reliable and even ineffective [43–45], and some national TB programmes, such as that of India, have clearly defined the DOT supervisor as someone outside the family [45].
How AMDT “helps” [17] a patient to complete a full course of treatment. Is the person who accompanies expected to observe the patient swallow each monthly dose of treatment?
How to train and supervise health workers who deliver AMDT.

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

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

Defaulter

A defaulter has been defined as a patient who has not collected MDT treatment for 12 consecutive months [15]. This is a purely arbitrary decision. It has been recommended that defaulters who cannot be retrieved be removed from the register [15], and that the register should be updated at least annually [15,16]. Consequently, removing defaulters from the register has become one of the important mechanisms to reduce the leprosy prevalence rate.

However, a significant proportion of so-called defaulters have not really disappeared from the community, so indiscriminately removing them from the register, as if they never existed, is not a reasonable solution. First of all, every effort should be made to prevent the absentee becoming a defaulter. A serious attempt should be made to trace absentees, beginning at the time of their first absence. Regarding those who have already become defaulters, depending on the reason for default, different actions should be taken. Those who have died or permanently migrated from the country should be removed from the register, whereas those who have moved out of the district or are taking treatment elsewhere should be transferred rather than removed from the register. For the remaining defaulters, whatever the reason for default, as long as they continue to live in the district and have yet to complete the full course of MDT treatment, by definition they are “cases” [15,16] and may continue to be sources of transmission. Instead of being removed from the register, the programme should encourage the health workers, with the assistance of the local community, to actively retrieve all defaulters.

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

Chemoprophylaxis of leprosy [46]

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

Regimens for Chemoprophylaxis in Leprosy

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

Both dapsone [47–49] and acedapsone [51–53] have been found capable of providing significant, about 50%, protective effect against leprosy, but it is unclear whether sulfone may prevent the occurrence of lepromatous, or skin-smear positive, MB leprosy. If today there is a need to apply chemoprophylaxis in leprosy, sulfone is no longer appropriate because its bactericidal activity is too weak and therefore its duration of treatment has to be long, which would cause tremendous operational difficulties, especially poor adherence, while dapsone is no longer appropriate because resistance to this drug by M. leprae has become a widespread phenomenon since the end of 1970s [11].

In view of a number of facts and assumptions [46], two principles are proposed in developing newer generation prophylactic regimens:

the treatment should be administered in not more than a single dose
the regimen should always contain rifampicin.

Two different regimens have recently been tested for chemoprophylaxis: a single dose of the combination rifampicin-ofloxacin-minocycline, or ROM [57], and a single dose of rifampicin, either 25 mg/kg body weight [58] or 10 mg/kg [59]. Because a single dose of ROM appears to be no more bactericidal than a single dose of rifampicin alone [4], and furthermore, the small bacterial population in a subclinically infected subject does not require an accompanying drug to prevent selection of rifampicin-resistant mutants, the addition of ofloxacin and minocycline to rifampicin will unnecessarily increase the cost and risk of side effects. Therefore, it seems more reasonable to give a single dose of rifampicin alone for chemoprophylaxis.

In the only published trial of rifampicin chemoprophylaxis, a single dose of rifampicin alone, at a dosage of 25 mg/kg, was tested in Southern Marquesas Island [58]. After ten years of follow-up, it was concluded that the protective effect was only 35–40% [58].

Up to now, the effectiveness of the two different dosages of rifampicin has not been directly compared in the same clinical trial. Until there is clear evidence that a single 1500 mg dose of rifampicin is more bactericidal than, and as well tolerated as, a 600 mg dose, rifampicin should be administered for chemoprophylaxis in a dose of 600 mg.

With respect to the potential risk for emergence of rifampicin resistance following chemoprophylaxis with a single dose of rifampicin, the small bacterial population of a subclinically infected person is unlikely to include a single rifampicin-resistant mutant, and therefore the risk of rifampicin resistance is probably negligible. On the other hand, if, for whatever reason, the bacterial population size is larger than expected, and even includes rifampicin-resistant mutants, the emergence of rifampicin resistance is still very unlikely because a single dose of rifampicin is insufficient to select resistant mutants, as has been shown by the relapse of MB patients after a single dose of rifampicin [12,18].

Limitations of Chemoprophylaxis in Leprosy

The epidemiological profile of leprosy indicates that, to prevent a single case of leprosy, hundreds or even thousands of subjects need to be treated [50]. Whatever regimen is applied, if trying to cover an entire population with chemoprophylaxis, the direct and indirect costs will be prohibitively high with tremendous operational difficulties, whereas the yield will be rather limited [50,57,58], so chemoprophylaxis is unlikely to be applied as a routine method for leprosy control. If chemoprophylaxis is confined only to a high-risk sub-population, i.e. to household contacts of leprosy patients, the benefit will be only 15% [50] because the contribution of household contacts to the total number of new cases in a population is no more than 30% and the efficacy of chemoprophylaxis under routine conditions is 50% (bear in mind that the maximum achieved efficacy of chemoprophylaxis has been no more than 75% in ideal conditions). Thus, from the leprosy control point of view, confining chemoprophylaxis to high-risk sub-populations represents only a very modest contribution. On the other hand, because chemoprophylaxis has shown significant protective effect among high-risk individuals [47–50], it may offer individual benefits in situations of exceptionally high risk. Nevertheless, the effect of chemoprophylaxis will most likely be transitory and, after the effect has waned, the high-risk individual could immediately be re-infected with M. leprae as long as transmission persists. Therefore, the index case and all known leprosy patients in the local community must be covered by chemotherapy before chemoprophylaxis is begun.

References

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

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

3. Consigny S, etal (2000) Bactericidal activities of HMR 3647, moxifloxacin, and rifapentines against Mycobacterium leprae in mice. Antimicrobial Agents and Chemotherapy 44: 2919-2921.

4. Ji B, etal (1998) Bactericidal activity of a single-dose combination of ofloxacin plus minocycline, with or without rifampin, against Mycobacterium leprae in mice and in lepromatous patients. Antimicrobial Agents and Chemotherapy 42: 1115-1120.

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

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

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

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

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

10. (2002) Uniform MDT regimen for all leprosy patients. Protocol Geneva:World Health Organization .

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

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

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

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

15. (1997) A guide to eliminating leprosy as a public health problem Geneva:World Health Organization . (document number WHO/LEP/97.1)

16. (2000) Guide to eliminate leprosy as a public health problem Geneva:World Health Organization .

17. (2002) The final push strategy to eliminate leprosy as a public health problem. Questions and answers Geneva:World Health Organization .

18. Grosset JH, etal (1989) Study of 39 documented relapses of multibacillary leprosy after treatment with rifampin. International Journal of Leprosy 57: 607-614.

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

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

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

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

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

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

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

26. Maeda S, etal (2001) Multidrug resistant Mycobacterium leprae from patients with leprosy. Antimicrobial Agents and Chemotherapy 45: 3635-3639.

27. Sackett DL, Sackett DL, Haynes RB, (1976) Introduction. The magnitude of compliance and noncompliance. Compliance with therapeutic regimens Baltimore and London:Johns Hopkins University Press .

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

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

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

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

32. Ellard GA, (1981) Drug compliance in the treatment of leprosy. Leprosy Review 52: 201-213.

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

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

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

36. Ellard GA, etal (1974) Urine tests to monitor the self-administration of dapsone by leprosy patients. American Journal of Tropical Medicine and Hygiene 23: 464-470.

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

38. Ellard GA, etal (1988) Clofazimine and dapsone compliance in leprosy. Leprosy Review 59: 205-213.

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

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

41. (1997) Treatment of tuberculosis. Guidelines for national programmes Geneva:World Health Organization . (document number WHO/TB/97.220)

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

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

44. Mathema B, etal (2001) Tuberculosis treatment in Nepal: a rapid assessment of government centers using different types of patient supervision. International Journal of Tuberculosis and Lung Disease 5: 912-919.

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

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

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

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

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

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

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

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

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

54. Ji B, etal (1996) Bactericidal activities of combinations of new drugs against Mycobacterium leprae in nude mice. Antimicrobial Agents and Chemotherapy 40: 393-399.

55. Grosset JH, etal (1990) Clinical trials of pefloxacin and ofloxacin in the treatment of lepromatous leprosy. International Journal of Leprosy 58: 281-295.

56. Ji B, Grosset J, (1990) Recent advances in the chemotherapy of leprosy. Leprosy Review 61: 313-329.

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

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

59. Vijayakumaran P, etal (2000) Chemoprophylaxis against leprosy: expectations and methodology of a trial. Leprosy Review 71: S37-S41.

60. Gelber RH, Levy L, (1987) Detection of persisting Mycobacterium leprae by inoculation of the neonatally thymectomized rat. International Journal of Leprosy 55: 872-878.