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Opinion Article
Need and strategy for sentinel surveillance for
drug resistance in leprosy in India
PL Joshi, DM Thorat, PR Manglani
In the fight against leprosy drug resistance poses a serious impediment at a stage when there is dramatic decline in prevalence due to intensive and concerted chemotherapy intervention. Drug resistance in leprosy has been reported since 1964 for dapsone, 1976 for rifampicin and 1996 for ofloxacin. Recent reports and publications have indicated few instances of rifampicin resistance in several endemic areas. In light of reporting drug resistance in leprosy, the National Leprosy Eradication Programme (NLEP) in India has started collecting information on relapse cases from peripheral institutions. The data show quite significant number of relapse cases (328 in year 2008-09) reported from few endemic states. Comprehensive data on the magnitude of drug resistance are crucial to evaluate the efficacy of MDT and to maintain the effectiveness of the current leprosy control strategy. It has become a necessity to develop a surveillance system to keep a close vigil on drug resistance. PCR based assays have convincingly demonstrated that detection of rifampicin resistance by this method is a feasible and practical alternative to the mouse foot pad (MFP) assay and has practical application in India. Surveillance of drug resistance in leprosy can be carried out based on a sentinel surveillance model. Certain district hospitals and tertiary institutions can be identified as sentinel sites in endemic states where tissue samples can be collected and transported to the identified reference laboratories. Based on the suspected and confirmed relapsed cases reported, 12 states have been identified for inclusion under the surveillance of drug resistance in leprosy. These are Andhra Pradesh, Bihar, Chhattisgarh, Karnataka, Madhya Pradesh, Maharashtra, Orissa, Rajasthan, Tamilnadu, Uttar Pradesh, West Bengal and Delhi. Four reference laboratories have already been identified, one each in the states of Uttar Pradesh, Andhra Pradesh, Tamilnadu and Delhi. Tissue samples from sentinel sites would be sent to designated laboratories for conducting the DNA sequencing tests to confirm rifampicin resistance.
Key words : Drug resistance surveillance, Leprosy, India
Introduction
current decade. The annual new case detection (ANCD) has also shown decline since the year The fight against leprosy has been a great success 2002-03. For leprosy, a chronic disease with social in India mainly due to introduction of multidrug therapy (MDT) since 1983. Due to availability of impediment at a stage when there is dramatic decline in prevalence due to intensive and prevalence has declined remarkably during PL Joshi, MD, FAMS, Deputy Director General (Leprosy)
DM Thorat, MD, Assistant Director General (Leprosy)
PR Manglani, MBBS, National Consultant (DPMR)
Directorate General of Health Services (Central Leprosy Division), Ministry of Health and Family Welfare, Government of India,
342-A, Nirman Bhawan, New Delhi-110 011, India
Correspondence to : PL Joshi Email : [email protected]
concerted chemotherapy intervention (WHO day; lots of small, random differences almost like 2007). Recent reports have indicated few mistake can happen in any new microbe that gets instances of rifampicin resistance in several made. The differences are called mutations. endemic areas (Jacobson and Hastings 1976, Antibiotic resistance evolves via natural selection Guelpa-Lauras et al 1984, Grosset et al 1989, acting upon random mutation but it can also be Pfaltzgraff and Ramu 1994, Matsuoka et al 2000, engineered by applying an evolutionary stress on Maeda et al 2001, Matsuoka et al 2003, Norman a population. Acquired resistance that develops due to chromosomal mutation and selection is clofazimine have also been reported earlier but termed vertical evolution. Once such a gene is generated, bacteria can then transfer the genetic clofazimine resistance strains of M. leprae have information in a horizontal fashion (between Drug resistance is the reduction in effectiveness Drug resistance has been considered as a natural of a drug in curing a disease or improving a response to the selective pressure of the drug. patient’s symptoms. When the drug is not However, it is exacerbated by several factors, intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug antimicrobials, poor patient compliance and tolerance. More commonly, the term is used in poor quality of available drugs (McManus 1997). the context of diseases caused by pathogens. Pathogens are said to be drug resistant when antimicrobial agents - (i) interference with cell drugs meant to inhibit or kill them have reduced wall synthesis (ii) inhibition of protein synthesis effect. When an organism is resistant to more (iii) interference with nucleic acid synthesis and than one drug, it is said to be multidrug resistant (iv) inhibition of metabolic pathways. Accordingly, (MDR). Secondary or acquired resistance is a the four main mechanisms by which bacteria result of inadequate chemotherapy characterized exhibit resistance to antibiotics are- (i) drug by initial clinical improvement followed by inactivation (ii) alteration of target sites (iii) alteration of metabolic pathways and (iv) reduced Infection with drug resistant organisms spread by drug accumulation and sporulation. Generally, patients with relapsed secondary resistance is discontinuation of treatment and monotherapy play a major role in production of MDR bacilli. It is In the light of reports of drug resistance in leprosy, well known that irregular treatment leads to low the National Leprosy Eradication Program (NLEP) drug concentrations in blood or tissues. Low drug has started focusing on the problem. The data concentrations provide an opportunity for from different places show quite significant resistant mutants to survive and further mutate number of relapse cases reported from few into organisms with an even higher degree of endemic states (Table 1). Since rifampicin is the backbone of MDT regimens, it becomes important to monitor the emergence of Potential causes of drug resistance include - rifampicin-resistant mutants. It has become a necessity to develop a surveillance system to keep a close vigil on drug resistance.
adherence of patients to prescribed drug Mechanism of drug resistance
Microbes do not always make perfect copies of itself with billions of microbes being made every Drug resistance in leprosy in India Indiscriminate used of anti-microbial drugs in relapse in leprosy is defined as the re-occurrence of the disease at any time after the completion of Drug resistance in leprosy
a full course of treatment. Criteria for relapse in leprosy are as follow - Currently two drug regimens have been officially recommended by the WHO - Appearance of new skin lesion or new activity in previously existing skin lesions or new The finding of new skin lesion or previous Although these regimens are effective, the need lesion with a high skin smear bacterial index for new regimens that are more effective and (BI) containing solid staining bacilli. An operationally less demanding is being felt for increase in BI is regarded as the key indication many reasons. From the operational point of of the multiplication of M.leprae and the view, the duration of MDT-MB is too long. Two of morphological index (MI) is also considered a useful additional tool in the diagnosis of clofazimine are weak bactericidal and clofazimine has some unpleasant side effects. Besides, as Histological evidence of relapse in a skin or there is no clear indication that leprosy is a disappearing disease; the efforts to control leprosy or acid fast bacilli are found.
leprosy must be sustained and adapted to the present situation. Resistant M. leprae occur Relapse is diagnosed by the appearance of spontaneously as a result of mutational events definite new skin lesions and/or an increase in the and are present in wild strains of bacterial bacillary index (BI) of two or more units at any population that have never been exposed to any single site compared to BI taken at the same site at Identification of drug resistance in leprosy
Reported relapse cases in India
Treated leprosy patients presenting with fresh NLEP has initiated collection of data on relapse in lesions, yet signs of healing at other sites, suggest India since 2007-08. States are submitting data possible drug resistance. Much higher bacterial / regularly through monthly progress report. The morphological indices obtained from skin smears state wise number of relapse cases reported in of apparently healed areas and fresh lesions India in 2008-09 is given in Table 1. However, support a diagnosis of drug resistance. It is there is practically very little information of relatively easy to diagnose secondary drug prevalence and incidence of drug resistance in resistance in multibacillary (MB) patients than in leprosy. Comprehensive data on the magnitude of drug resistance are crucial to evaluate the efficacy of MDT and to maintain the effectiveness of the Drug resistance should be suspected when- 1. There is no response to chemotherapy and Surveillance of drug resistance
Surveillance of drug resistance in leprosy can be carried out based on a sentinel surveillance Proper identification of relapse cases and to model. Certain district hospitals and tertiary monitor trends over a period of time is essential institutions can be identified as sentinel sites in in the process of controlling drug resistance. A endemic states where tissue samples can be Table 1: Number of relapse cases reported
detect secondary rifampicin resistance among by the states during the year 2008-09
patients who have relapsed after completing a full States and UTs
No. of relapse cases
course of treatment with MDT for MB leprosy. The inclusion of dapsone resistance would further enhance the preparedness to face rifampicin resistance. At present, molecular methods to identify clofazimine resistance are still not It would be highly desirable to have a rapid, simple technique for monitoring suspected cases of rifampicin resistance that could be applied directly to clinical specimens. During the last 15 years several PCR based assays/ techniques have been developed have been developed for the detection of rifampicin resistance. Application of such methods shows that molecular methods are feasible and practical alternative to the mouse foot pad (MFP) assay and has practical application in countries where leprosy burden is relatively Molecular genetic tests provide a rapid screening tool for detection of majority of resistant isolates. As this test detects only nucleotide mutations, it can not distinguish silent amino acid changes from those that result in amino acid substitution. The rapidity and ease of interpretation of the PCR assay(s) compared with MFP assay is an important finding and supports the potential use of this assay. Published results suggest that MARS assay is rapid and simple to implement and could be performed for detecting rifampicin resistant M.leprae. (Guelpa-Lauras et al 1984).
In a study specimens from 59 relapse cases from Colombia (2006-2008), Indonesia (2000-2005) and Myanmar (2005-2007) were tested by DNA sequencing (WHO 2009) and the result shows mutation in 14 cases as given in Table 2.
Source - MPR, Central Leprosy Division, DGHS, Delhi
The sentinel surveillance system
collected and transported to the identified It could comprise of two parts- (i) the first reference laboratories. component is the systematic collection of samples from identified relapse cases in the field and transportation of samples to the respective combat leprosy and tuberculosis. The main aim of reference laboratory. The specimens can be the sentinel surveillance system should be to collected systematically at the identified sentinel Drug resistance in leprosy in India Table 2: Detection of dapsone and rifampicin
skin smear contains enough bacilli for polymerase resistance by DNA sequencing
Laboratory tests
Mutation Mutation
Nucleotide sequencing of the drug resistance determining region in the rpoB for rifampicin and dapsone rifampicin
folP genes for dapsone respectively can be done using PCR and direct sequencing. Isolates with amino acid substitution in one or more drug resistance determining regions, which have been confirmed to confer rifampicin and dapsone resistance by the mouse footpad method, should be scored as resistant to the respective drug(s).
sites. (ii) the second component is the laboratory Quality control of the reference laboratories that part which can be carried out by identified referral are carrying out DNA sequencing for rifampicin laboratories (sentinel surveillance centres) resistance could be conducted following standard receiving samples from the field and carrying out procedures. A tertiary institute can be identified test for rifampicin and dapsone resistance. to conduct quality control in sentinel sites. Quality The surveillance activity can be carried out in checks are needed from time to time regarding selected endemic states that are currently patient selection, data entry and transportation detecting significant numbers of new leprosy cases annually. Surveillance activity should be an Reference laboratories (sentinel surveillance
ongoing activity and participating laboratories centres)
will need to take into account the need to Four reference laboratories have already been maintain the sentinel surveillance work over a identified, one each in the states of Uttar Pradesh period of time. Each sentinel surveillance centre (National JALMA Institute for Leprosy and Other (SSC) can be allotted specified state areas from Mycobacterial Diseases, Agra), Andhra Pradesh where tissue specimens could be sent routinely. (Blue Peter Research Centre, Hyderabad), MB relapse cases referred to the selected referral Tamilnadu (Schieffelin Institute of Health facilities need to be examined by an expert Research and Leprosy Centre, Karigiri) and Delhi (Stanely Brown Laboratory, Shahdara Leprosy Physician) to confirm the diagnosis of relapse Hospital, The Leprosy Mission, Nand Nagari, using strict criteria so as to reduce selection bias. Delhi) where tissue samples would be sent from Criteria for inclusion of MB relapse cases
sentinel sites for conducting the DNA sequencing A person who was initially classified as an MB case and has taken at least 12 monthly doses of MB- MDT as recommended by WHO and who is now Sentinel sites in selected states
showing signs and symptoms of relapse without Based on the suspected and confirmed relapsed any evidence of lepra reaction. MB classification is cases reported, 12 states have been identified for based on having 6 and more skin lesions or being inclusion under the surveillance of drug skin smear result positive at any single site. From resistance in leprosy. These are Andhra Pradesh, each case, 4 slit-skin smear samples will be Bihar, Chhattisgarh, Karnataka, Madhya Pradesh, required to be collected. Each sample could be Maharashtra, Orissa, Rajasthan, Tamilnadu, Uttar taken from a different skin lesion that is most prominent. Tissue scraping collected from a slit- Reporting and dissemination of information
Grosset JH, Guelpa-Lauras CC, Bobin P et al (1989). Study of 39 documented relapses of multibacillary leprosy Each sentinel surveillance centre (SSC) would be after treatment with rifampin. Int J Lepr Other Mycobact required to take necessary steps to inform the Dis. 57: 607-614.
health facility where the MB relapse patient will Jacobson RR and Hastings RC (1976). Rifampin-resistant be under gone treatment for information and leprosy. Lancet.2: 1304-1305.
further action. Reference labs should also send a Pfaltzgraff RE and Ramu G (1994). Clinical leprosy. In: copy of the results along with case report forms Leprosy, 2 edn, (Hastings RC and Opromolla DV, eds), submitted to them by various participating Churchill Livingstone, Edinburgh, pp 237-287.
sentinel sites to tertiary institute identified for Matsuoka M, Kashiwabara Y and Namisato M (2000). A Mycobacterium leprae isolate resistant to dapsone, quality control, data compilation and analysis rifampin, ofloxacin and sparfloxacin. Int J Lepr Other every month. Institute would then submit an Mycobact Dis. 68: 452-455.
annual report of all the samples tested and the Maeda S, Matsuoka M, Nakata N et al (2001). Multidrug results to the Global Leprosy Programme, WHO resistant Mycobacterium leprae from patients with with a copy to the Central Leprosy Division, leprosy. Antimicrob Agents Chemother. 45: 3635-3639.
Matsuoka M, Kashiwabara Y, Zhang L et al (2003). A second case of multidrug-resistant Mycobacterium Management of MB relapse cases
leprae isolated from a Japanese patient with relapsed All MB relapse cases included in the surveillance lepromatous leprosy. Int J Lepr Other Mycobact Dis.71:
study should immediately be put on treatment with standard MB-MDT without waiting for the McManus MC (1997). Mechanism of bacterial resistance to antimicrobial agents. Am J Health Syst Pharm. results on the status of drug resistance from the 54:1420-1433.
SSC Laboratory. If the result comes back as Norman G, Joseph G, Ebenezer G et al (2003). Secondary sensitive to rifampicin, MB-MDT treatment is to rifampin resistance following multi-drug therapy-a case be continued accordingly. Should patients be report. Int J Lepr Other Mycobact Dis. 71: 18-21.
reported to be resistant to dapsone only, standard 10. Williams DL and Gillis TP (2004). Molecular detection of MB-MDT is to be continued. In case the laboratory drug resistance in Mycobacterium leprae. Lepr Rev. 75:
report that the patient is harbouring rifampicin resistant M.leprae, the new regimen of MDT 11. World Health Organization (2007). Informal consultation on rifampicin resistance in leprosy. National JALMA Institute of Leprosy and Other Mycobacterial Diseases. References
Lepr Rev. 78: 295-305.
Guelpa-Lauras CC, Grosset JH, Constant-Desportes M et 12. World Health Organization (2009). Drug resistance in al (1984). Nine cases of rifampicin-resistant leprosy. Int J leprosy: reports from selected endemic countries. Wkly Lepr Other Mycobact Dis. 52: 101-102.
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Source: http://www.leprosy-info.org/sites/default/files/JOSHI2009.pdf

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