|Year : 2021 | Volume
| Issue : 6 | Page : 791-795
Drug resistance in Mycobacterium Leprae in the context of zero leprosy
Itu Singh, Utpal Dr. Sengupta
Department of Molecular Biology, Stanley Browne Laboratory, The Leprosy Mission Community Hospital – Nand Nagri, New Delhi, India
|Date of Submission||27-Sep-2021|
|Date of Decision||12-Oct-2021|
|Date of Acceptance||13-Oct-2021|
|Date of Web Publication||22-Nov-2021|
Utpal Dr. Sengupta
Stanley Browne Laboratory, The Leprosy Mission Community Hospital – Nand Nagri, New Delhi - 110 093
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Singh I, Sengupta UD. Drug resistance in Mycobacterium Leprae in the context of zero leprosy. Indian Dermatol Online J 2021;12:791-5
|How to cite this URL:|
Singh I, Sengupta UD. Drug resistance in Mycobacterium Leprae in the context of zero leprosy. Indian Dermatol Online J [serial online] 2021 [cited 2022 Jan 26];12:791-5. Available from: https://www.idoj.in/text.asp?2021/12/6/791/330821
Leprosy is a chronic infectious disease caused by Mycobacterium leprae and/or by Mycobacterium lepromatosis., The disease mainly affects the peripheral nerves, skin, and mucous membranes and if left untreated it may lead to nerve damage and deformity. Use of diamino diphenyl sulphone (DDS), also called dapsone, for treatment of leprosy began in 1945 and DDS monotherapy continued till the appearance of primary and secondary DDS resistance during the 1970s., Most of these DDS-resistant cases originated from fully treated relapse cases. However, it was noted that low doses of dapsone and irregular treatment were the major causes of relapse. Later when rifampicin, a bactericidal drug, was tried in a mono-therapeutic mode, M. leprae developed resistance also to this drug. Considering the above, the multidrug therapy (MDT) approach was adopted like tuberculosis chemotherapy in leprosy elimination by combining DDS with bactericidal drug, rifampicin, and an anti-bacterial drug, clofazimine with anti-inflammatory activity. After finding this MDT combination effective in curing leprosy, it was implemented in 1982 worldwide by the World Health Organization (WHO) for the elimination of leprosy. Because of this robust MDT regimen, the prevalence of leprosy was brought down to <1 case/10,000 population (an elimination figure assigned by WHO) by the year 2002 worldwide. Similarly, in India, the prevalence of leprosy which was 25.9/10,000 in 1991 was brought down to <1/10,000 in 2005 after the introduction of MDT under the elimination program.
During this critical juncture of elimination, WHO has drawn up a strategical road map from the year 2021 to 2030 focussing toward Zero leprosy target. However, at the moment although the prevalence of leprosy has gone down to 0.22/10,000 worldwide and to 0.66/10,000 in India, a total number of 202,185 new cases including 14,981 child cases are appearing in the world. India is still housing 114,451 (57%) of these new cases of the world. These data clearly indicate that despite the continuation of effective chemotherapeutic preventive measures by MDT for more than 4 decades, the transmission of the disease is continuing in the community. Leprosy being a chronic disease with a known long period of incubation (>20 years), a total elimination program with Zero leprosy target by 2030 may be too optimistic. For any elimination/eradication program of an infectious chronic disease such as leprosy, effective chemotherapy with 100% full cure of the disease is one of the most important aspects of a control measure. The disease being dynamic in nature with a range of clinical manifestations exhibited by the host in response to infection has been well classified by Ridley and Jopling based on a bacteriological and immuno-histological scale. However, for making the treatment procedure very handy at the field level, the disease manifestation has been simplified and classified by WHO as paucibacillary (PB = presence of 1–5 skin lesions) and multibacillary (MB = presence of >5 skin lesions) and recommended treatment of the disease with 12 months of MDT for MB and 6 months of MDT for PB cases. Further, as the bacterial index (BI) and the activity of the lesions are not seriously considered at the field level, the patients are considered as cured cases and are released from treatment after the completion of fixed-dose MDT. MB cases harboring a wide range in M. leprae population varying between 1+ and 5+ BI receive 12 monthly doses of 600 mg each of the bactericidal drug, rifampicin which has a half-life of only two and half hours. It has been shown that despite full treatment with MDT for 2 or 3 years, M. leprae is able to persist as viable bacilli as shown by the growth in mouse footpad (MFP) or by measuring adenosine triphosphate levels using bioluminescence assay.,, Later, the presence of viable M. leprae has also been reported from fully treated PB cases also with a history of relapse. In addition, it is also not very uncommon to find defaulters during the course of MDT. The percentage of nonadherence to fixed-dose MDT (defaulters) varied between ≈50% and ≈60% and has been noted predominantly in patients with MB.,, Hence, it was expected that relapses would occur from the pool of defaulters or from fully treated leprosy cases due to the growth of the remaining viable M. leprae bacilli which have not been killed by MDT. A recent cohort study conducted by our group in the Leprosy Mission Hospitals in India on MB patients with high BI (≥3+) showed the presence of viable M. leprae employing quantitative reverse transcription-polymerase chain reaction for the gene expression level of hsp18 gene (encoding the heat shock 18 kDa protein) and esxA gene (encoding ESAT-6 protein) which were found to correlate with the exponential growth of M. leprae in MFP in skin biopsies from fully treated cases (Under publication). The remaining viable bacilli in such fully treated highly bacillated MB cases will be able to grow because in such patients' cell-mediated immunity to M. leprae remain suppressed for a long time. If these relapse cases are not diagnosed and treated immediately, they will act as a source of infection and will be responsible for the transmission of the disease in the community.
Earlier relapses during DDS monotherapy,,, associated with the emergence of both primary and secondary drug resistance to DDS, sufficiently delayed the progress of the leprosy control program till MDT with the bactericidal drug rifampicin was launched in 1982. Now, after more than 4 decades of MDT, relapses are often being noted due to drug resistance against rifampicin. Resistance to rifampicin and other bactericidal drugs such as ofloxacin has been reported from most of the leprosy endemic countries such as Brazil, China, Colombia, Malaysia, Korea, Myanmar, Indonesia, Philippines, Japan, and India.,,,,,,, A recent study in Colombia showed a significantly higher percentage of resistance to rifampicin in newly diagnosed cases as compared with treated cases. Considering the gravity of the situation, WHO initiated a multicentric study which continued for 10 years to look for the distribution of drug resistance in the endemic countries of the world. It was noted that of 1143 relapses 58 (5.1%) and of 789 new MB cases, 16 (2%) were resistant to rifampicin. These studies clearly indicated that the rifampicin-resistant strain is transmitting the disease in the community. These results immediately directed WHO to take an account of the background data on antimicrobial resistance (AMR) through a global consultation of the experts of leprosy endemic countries without any data for drug resistance between 2014 and 2020 from India which holds >50% of the world population of leprosy cases. Further, WHO has recently organized a virtual meeting of the global experts and presented AMR surveillance data from all the endemic countries and considered that threat due to AMR is not yet there and hence leprosy elimination program can continue with the first-line drug regimen. However, it was decided that the continuation of AMR surveillance following the WHO guidelines should be continued.
Although relapse in leprosy gathered momentum for search for the occurrence of AMR from cases of relapse and was taken as a probable strong indicator for patients being resistant to MDT, around the same time, there were reports of the occurrence of drug resistance from recurrent reactional cases (both type 1 and type 2) by various tertiary care hospitals.,,,, Although type 1 reactions may occur in about 20–40% of MB leprosy cases,,,,,, type 2 reactions [or erythema nodosum leprosum (ENL)] have been reported in about 10% of borderline lepromatous and from more than 50% in lepromatous leprosy cases. All these studies strongly indicate that patient manifesting reactions is a very common phenomenon during therapy and after completion of MDT and therefore, reactional patients should be screened for M. leprae drug-resistant strains under the leprosy elimination program. Further, a recent retrospective cohort study showed that M. leprae drug-resistant strains for all three drugs may also be associated with neuropathy in leprosy.
In the background scenario of the emergence of M. leprae-resistant strains during MDT therapy and post-MDT therapy, various research groups are engaged in reducing the transmission of leprosy with a chemotherapeutic approach by administration of single-dose rifampicin (SDR) as a leprosy post-exposure prophylaxis (LPEP) measure to contacts of newly diagnosed leprosy cases. Therefore, in 2008 a cluster-randomized placebo control double-blind trial in Bangladesh named contact transmission and chemoprophylaxis in leprosy was conducted. It was noted that SDR was effective for the first 2 years in reducing the incidence by 57%. However, after 2 years there was no difference in the protective efficacy for leprosy between the SDR and placebo control groups. During the DDS monotherapy era in the 1960s and 1970s, chemoprophylaxis trials were also conducted in Uganda and India with the administration of contact population with dapsone and acedapsone, respectively, for the control of leprosy. These trials although showed about 85% decline in the prevalence of leprosy but ultimately the protective efficacy waned with time as there was no effect of dapsone chemoprophylaxis on the incidence of leprosy. Further, during that time reports on the rise in dapsone resistance cases in the population also did not favor the implementation of dapsone chemoprophylaxis in the control program.,,,,,, Although SDR chemoprophylaxis of contacts of newly diagnosed patients did not show any difference in protective efficacy after 2 years between the SDR and placebo group, the SDR chemoprophylaxis was introduced into the program because of its immediate protective effect on the development of leprosy in the newly diagnosed leprosy contact population of the world for ultimate reduction in transmission of infection and consequently in the emergence of new leprosy cases in the world. Initially, a feasibility study conducted for the implementation of SDR to the contacts of newly diagnosed patients under the control program in Brazil, India, Indonesia, Myanmar, Nepal, Sri Lanka, and Tanzania showed that LPEP with SDR is well tolerated and can be easily implemented in the leprosy control program of the endemic countries. Following this, SDR has been implemented under the direction of WHO in the elimination program in 2018 in all endemic countries worldwide.
From the above, it is clear that secondary and primary resistance to rifampicin and ofloxacin are on the rise which has been established by screening relapse and newly diagnosed MB cases from the leprosy endemic countries.,,,,,,,,, Further, the annual records also show a gradual rise of relapse cases (from 2844 of 2016 to 3897 of 2019),, under the elimination program. In addition, reports of isolation of rifampicin drug-resistant strains from both type 1 and type ENL cases which are being reported from various research groups are of great concern as this has not been taken up yet in the M. leprae-resistant strain surveillance mechanism under the program. As leprosy cases with reactions are difficult to treat under field conditions, these cases are mostly referred to and treated in tertiary care hospitals having indoor facilities. All these findings strongly indicate that both rifampicin and ofloxacin-resistant M. leprae strains released from the relapse and reaction cases are slowly spreading infection in the endemic population. Introduction of SDR in such a situation might induce more drug pressure and might help M. leprae strain to become more resistant to the prescribed drugs and could further help in the survival of M. leprae-resistant strain in the endemic community for the propagation of infection for a long time to come. Although the problem of AMR is now very focal in distribution, the drug pressure in the community might rather help in further maintenance and propagation of AMR strain in the community.
Therefore, the WHO strategic plan “Toward Zero leprosy by 2030” might direct its priority to monitor both relapses and reactions in leprosy which are occurring due to drug-resistant M. leprae to the primary bactericidal drug rifampicin and the second-line drugs, ofloxacin and clarithromycin. Although most of the resistant cases have been reported in patients who have relapsed after MDT indicated the appearance of secondary drug resistance to either rifampicin or ofloxacin or both;, however, the emergence of primary drug resistance to rifampicin and ofloxacin in an endemic population is an early indication for drug-resistant M. leprae strain transmission in the community. It has been often mentioned that the relapse rate in the community is very low and hence it will not have much impact on the leprosy elimination program. However, it may be emphasized that report of relapse and reaction in the community is generally late and mostly the cases land up in tertiary care hospitals because of their need for personalized treatment. Considering the above points mentioned, the journey toward Zero leprosy by 2030 may not be attainable without directing its priority to the establishment of a robust surveillance mechanism for relapse and reactions in leprosy.
Therefore, it is recommended that the following strategy should be adopted immediately to check the transmission of AMR strains of M. leprae in the endemic community are as follows:
- Establishment of a robust setup for early diagnosis of relapse and reactions in leprosy at the field level and their molecular screening for mutations for drug resistance to DDS, rifampicin, ofloxacin, and clarithromycin.
- Screening of all new MB cases for the presence of molecular mutations for primary drug-resistant strains to DDS, rifampicin, ofloxacin, and clarithromycin.
- Once a drug resistance case to the above drugs is identified, the close contacts in the family should be screened for early detection of transmission of drug-resistant M. leprae strains in the family.
- After identification of either primary or secondary drug-resistant cases, the patient should be treated adequately with an alternative regimen for the cure of leprosy.
The authors acknowledge the staff of SBL and TLMTI for their help.
| References|| |
Irgens LM. The discovery of the leprosy bacillus. Tidsskr Nor Laegeforen 2002;122:708-9.
Han XY, Seo YSH, Sizer KC, Schoberle T, May GS, Spencer JS, et al
. A new Mycobacterium species causing diffuse lepromatous leprosy. Am J Clin Path 2008;130:856-64.
Zhu YI, Stiller MJ. Dapsone and sulfones in dermatology: Overview and update. J Am Acad Dermatol 2001;45:42034.
Pearson J, Rees R, Waters M. Sulfone resistance in leprosy. A review of 100 proven clinical cases. Lancet 1975;2:69-72.
Pearson JM, Haile GS, Rees RJ. Primary dapsone-resistant leprosy. Lepr Rev 1977;48:129-32.
Jacobson RR, Hastings RC. Rifampin-resistant leprosy. Lancet 1976;2:1304-5.
Cohn ML, Middlebrook G, Russell WF Jr. Combined drug treatment of tuberculosis. I. Prevention of emergence of mutant populations of tubercle bacilli resistant to both streptomycin and isoniazid in vitro
. J Clin Invest 1959;38:1349-55.
WHO. Chemotherapy of Leprosy for Control Programmes. Geneva: World Health Organization; 1982.
Sengupta U. Elimination of leprosy in India: An analysis. Ind J Dermatol Leprol 2017;84:131-6.
WHO. Towards Zero Leprosy. Global Leprosy (Hansen's Disease) Strategy 2021-2030.
WHO. Weekly Epidemiological Report 2020;95:417-40.
Lockwood DNJ, Suneetha S. Leprosy: Too complex a disease for a simple elimination paradigm. Bull World Health Organ 2005;83:230-5.
Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J lepr Other Mycobact Dis 1966;34:255-73.
Acocella G. Clinical pharmacokinetics of rifampicin. Cin Pharmacokinet 1978;3:108-27.
Ebenezer GJ, Daniel S, Norman G, Daniel E, Job CK. Are viable Mycobacterium leprae
present in lepromatous patients after completion of 12 months' and 24 months' multi-drug therapy? Indian J Lepr 2004;76:199-206.
Gupta UD, Katoch K, Singh HB, Natarajan M and Katoch VM. Persister studies in leprosy patients after multidrug treatment. Int J Lepr Other Mycobact Dis 2005;73:100-4.
Shetty VP, Suchitra K, Uplekar MW, Antia NH. Persistence of Mycobacterium leprae
in the peripheral nerve as compared to the skin of multi-drug treated leprosy patients. Lepr Rev 1992;63:329-36.
Shetty VP, Wakade A, Antia NH. A high incidence of viable Mycobacterium leprae
in post-MDT recurrent lesions of tuberculoid leprosy patients. Lepr Rev 2001;72:337-44.
Griffiths S, Ready N. Defaulting pattern in a provincial leprosy control programme in Northern Mozambique. Lepr Rev 2001;72:199-205.
Rao PSS. A study on non-adherence to MDT amongst leprosy patients. Ind J Lepr 2008;80:149-54.
Raju MS, Elkana M, Failbus P, Palla JP, Hembrom UK, Rao, PS. Correlates of defaulting from MDT among leprosy patients. Ind J Lepr 2015;87:241-8.
Davis GL, Ray NA, Lahiri R, Gillis TP, Krahenbuhl JL, Williams DL, et al
. Molecular assays for determining Mycobacterium leprae
viability in tissues of experimentally infected mice. PLoS Negl Trop Dis 2013;7:e2404. doi: 10.1371/journal.pntd. 0002404.
Mitra DK, Joshi B, Dinda AK, Rai AK, Girdhar BK, Katoch K, et al
. Induction of lepromin reactivity in cured lepromatous leprosy patients: Impaired chemokine response dissociates protective immunity from delayed type of hypersensitivity. Microbes Infect 2009;11:1122-30.
Shetty VP, Wakade AV, Ghate SD, Pai VV, Ganapati RR, Antia NH. Clinical, histopathological and bacteriological study of 52 referral MB cases relapsing after MDT. Lepr Rev 2005;76:241-52.
Kar HK, Sharma P. New lesions after MDT in PB and MB leprosy. Ind J lepr 2008;80:247-55.
Cartel JL, Naudillon Y, Remy JC, Grosset JH. Contribution of relapses to total infection sources of leprosy in Guadeloupe. Lepr Rev 1987;58:339-48.
The Leprosy Unit, WHO. Risk of relapse in leprosy. Indian J Lepr 1995;67:13-26.
Rocha A da S, Cuhna MdG, Diniz LM, Salgado C, Aires MEP, Nery JA, et al
. Drug and multiple resistance among Mycobacterium leprae
isolates from Brazilian relapsed leprosy patients. J Clin Microbiol 2012;50:1912-17.
Chokkakula S, Chen Z, Wang L, Jiang H, Chen Y, Zhang W, et al
. Molecular surveillance of antimicrobial resistance and transmission pattern of Mycobacterium leprae
in Chinese leprosy patients. Emerg Microbes Infect 2019;8:1479-89.
Beltran-Alzate C, Diaz FL, Romero-Monoya M, Sakamuri R, Li W, Kimura M, et al
. Leprosy drug resistance surveillance in Colombia: The experience of a sentinel country. PLoS Negl Trop Dis 2016;10:e0005041.
Dalawi I, Tang MM, Osman AS, Ismail M, Bakar RSA, Dony JF, et al
. Drug resistance pattern of Mycobacterium leprae
from mouse foot pad cultivation between 1997-2013 in Malaysia. Lepr Rev 2017;88:463-77.
You EY, Kang TJ, Kim SK, Lee SB, Chae GT. Mutations in genes related to drug resistance in Mycobacterium leprae
isolates from leprosy patients in Korea. J Infect 2005;50:6-11.
Matsuoka M, Budiawan T, Aye KS, Kyaw K, Tan EV, Cruz ED, et al
. The frequency of drug resistance mutations in Mycobacterium leprae
isolates in untreated and relapsed leprosy patients from Myanmar, Indonesia and the Philippines. Lepr Rev 2007;78:343-52.
Lavania M, Jadhav RS, Chaitanya VS, Turankar R, Selvasekhar A, Das L, et al
. Drug resistance pattern in Mycobacterium leprae
isolates from relapsed leprosy patients attending The Leprosy Mission (TLM) Hospitals in India. Lepr Rev 2014;85:177-85.
Lavania M, Nigam A, Turankar RP, Singh I, Gupta P, Kumar S, et al
. Emergence of primary drug resistance to rifampicin in Mycobacterium leprae
strains from leprosy patients in India. Clin Mirobiol Infect 2015;21:e85-6.
Guerrero MI, Colorado CL, Torres JF, Leon CI. Is drug-resistant Mycobacterium leprae
a real cause of concern? First approach to molecular monitoring of multibacillary Colombian patients with and without previous leprosy treatment. Biomedica 2014;34:137-47.
Cambau E, Saunderson P, Matsuoka M, Cole ST, Kai M, Suffys P, et al
. Antimicrobial resistance in leprosy: Results of the first prospective open survey conducted by WHO surveillance network for the period 2009-2015. Clin Microbiol Infect 2018;24:1305-10.
WHO. Antimicrobial resistance in leprosy. Report of a global consultation. 27-28 October, 2016.
WHO. Anti-microbial resistance in leprosy. Report of the virtual consultation. 14-17 June, 2021, New Delhi, India. Document no.: SEA/GLP/7.
Turankar RP, Lavania M, Singh I, Ahuja M, Pathak VK, Singh V, et al
. In Symposium on “Relapse and drug resistance in leprosy: Present scenario and critical issues.” Session II. Criteria for sending biopsy for drug resistance test. Kumar A and Nayak R. Ind J Lepr 2018;90:79-93.
Sardana K, Mathachan SR, Agrawal D, Lavania M, Ahuja M. Late reversal reaction with resistant Mycobacterium leprae
: An emerging paradigm. Trop Doc 2020;50:77-81.
Arora P, Sardana K, Agarwal A, Lavania M. Resistance is a cause for chronic steroid dependent ENL-a novel paradigm with potential implications in management. Lepr Rev 2019;90:201-5.
Sardana K, Kulhari A, Mathachan SR, Khurana A, Bansal P, Ahuja A, et al
. Late leprosy reaction presenting as erythema multiforme-like erythema nodosum leprosum with underlying rifampicin resistance and its potential implications. Int J Mycobacteriol 2020;9:226-8.
] [Full text]
Narang T, Kamat D, Thakur V, Lavania M, Singh I, Ahuja M. Equal rates of drug resistance in leprosy cases with relapse recurrent/chronic type 2 reaction; Time to revise the guidelines for drug resistance testing in leprosy. Clin Exp Dermatol 2021. doi: 10.1111/ced. 14884. Epub ahead of print.
Hungria EM, Buhrer-Sekula S, de Oliveira RM, Aderaldo LC, Pontes AA, Cruz R, et al.
Leprosy reactions: The predictive value of Mycobacterium leprae-specific serology evaluated in a Brazilian cohort of leprosy patients (U-MDT/CT-BR). PLoS Negl Trop Dis 2017;11:e0005396. doi: 10.1371/journal.pntd. 0005396.
Smith WC, Nicholls PG, Das L, Barkataki P, Suneetha S, Suneetha L, et al
. Predicting neuropathy and reactions in leprosy at diagnosis and before incident events—results from the INFIR cohort study. PLoS Negl Trop Dis 2009;3:e500. doi: 10.1371/journal.pntd. 0000500.
Ranque B, Nguyen VT, Vu HT, Nguyen TH, Nguyen NB, Pham XK, et al
. Age is an important risk factor for onset and sequelae of reversal reactions in Vietnamese patients with leprosy. Clin Infect Dis 2007;44:33-40.
Scollard DM, Smith T, Bhoopat L, Theetranont C, Rangdaeng S, Morens DM. Epidemiologic characteristics of leprosy reactions. Int J Lepr Other Mycobact Dis 1994;62:559-67.
Ponnighaus JM, Boerrigter G. Are 18 doses of WHO/MDT sufficient for multibacillary leprosy; results of a trial in Malawi. Int J Lepr Other Mycobact Dis 1995;63:1-7
Penna GO, Buhrer-Sekula S, Kerr LRS, Stefani MMA, Rodrigues LC, de Araujo MG, et al
. Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): Results of an open label, randomized and controlled clinical trial, among multibacillary patients. PLoS Negl Trop Dis 2017;11:e0005725.
Pocaterra L, Jain S, Reddy R, Muzaffarullah S, Torres O, Suneetha S, et al
. Clinical course of erythema nodosum leprosum: An 11-year cohort study in Hyderabad, India. Am J Trop Med Hyg 2006;74:868-79.
Saunderson P, Gebre S, Byass P. ENL reactions in the multibacillary cases of the AMFES cohort in central Ethiopia: Incidence and risk factors. Lepr Rev 2000;71:318-24.
Mahajan NP, Lavania M, Singh I, Nashi S, Preethish-Kumar V, Vengalil S, et al
. Evidence of Mycobacterium leprae
drug resistance in a large cohort of leprous neuropathy patients from India. Am J Trop Med Hyg 2020;102:547-52.
Richardus JH, Tiwari A, Barth-Jaeggi T, Arif MA, Banstola NL, Baskota R, et al
. Leprosy post-exposure prophylaxis with single dose rifampicin (LPEP): An international feasibility programme. Lancet Glob Health 2021;9:e81-90.
Moet FJ, Pahan D, Oskam L, Richardus JH. Effectiveness of single dose rifampicin in preventing leprosy in close contacts of patients with newly diagnosed leprosy: Cluster randomised controlled trial. BMJ 2008;336:761-4.
Wardekar RV. DDS prophylaxis against leprosy. Lepr India 1967;39:155-9.
Noordeen SK. Chemoprophylaxis in leprosy. Lepr India 1969;41:247-54.
Noordeen SK, Neelan PN. Chemoprophylaxis among contacts of non-lepromatous leprosy. Lepr India 1976;48:635-42.
Noordeen SK. Long term effects of chemoprophylaxis among contacts of lepromatous cases. Results of 8 1/2 years follow-up. Lepr India 1977;49:504-9.
Noordeen SK, Neelan PN. Extended studies on chemoprophylaxis against leprosy. Indian J Med Res 1978;67:515-27.
Neelan PN, Noordeen SK, Sivaprasad N. Chemoprophylaxis against leprosy with acedapsone. Indian J Med Res 1983;78:307-13.
Neelan PN, Sirumban P, Sivaprasad N. Limited duration acedapsone prophylaxis in leprosy. Indian J Lepr 1986;58:251-6.
WHO. 2018. Guidelines for the diagnosis, treatment and prevention of leprosy. ISBN: 978 92 9022 638 3.
WHO. Weekly Epidemiological Report, 2018;93:445-56.
WHO. Weekly Epidemiological Report, 2019;94:389-412.