|Year : 2020 | Volume
| Issue : 2 | Page : 115-123
Prevention of transmission of leprosy: The current scenario
Aparna Palit1, Hemanta Kumar Kar2
1 Department of Dermatology and Venereology, AIIMS, Bhubaneswar, Odisha, India
2 Department of Dermatology, Max Smart Super Specialty Hospital, New Delhi, India
|Date of Web Publication||22-Jan-2020|
Dr. Aparna Palit
Department of Dermatology and Venereology, AIIMS, Bhubaneswar, Odisha
Source of Support: None, Conflict of Interest: None
With the worldwide implementation of WHO multidrug therapy in the 1980s, the global burden of leprosy has decreased. However, the annual new case detection rate around the world has remained nearly static over the past decade with India, Brazil, and Indonesia contributing the majority of these new cases. This has been attributed to the ongoing transmission of Mycobacterium leprae from existing untreated cases and partly to the intensive new case detection programs operative in endemic areas. The WHO has called for a “global interruption of transmission of leprosy by 2020”. Targeted chemoprophylaxis of contacts may help bring down the number of new cases. The single-dose rifampicin currently in use for post-exposure prophylaxis (PEP) has limitations and so newer antileprosy drugs and regimens have been trialed for chemoprophylaxis. BCG re-vaccination in combination with chemoprophylaxis for the prevention of leprosy transmission has not been very encouraging. The use of the anti-phenolic glycolipid-1 (PGL-1) antibody test to detect subclinical cases and administer targeted chemoprophylaxis was unsuccessful owing to its low sensitivity and technical difficulties in a field setup. There is a pressing need for newer multidrug chemoprophylactic regimens using second-line antileprosy drugs. The Netherlands Leprosy Relief has proposed an enhanced PEP++ regimen. A simple but highly sensitive and specific serological test to detect subclinical cases at the field level needs to be developed. Although there are a number of challenges in the large-scale implementation of strategies to halt leprosy transmission, it is important to overcome these in order to move towards a “leprosy-free world.”
Keywords: Chemoprophylaxis, immunoprophylaxis, leprosy, PEP++regimen
|How to cite this article:|
Palit A, Kar HK. Prevention of transmission of leprosy: The current scenario. Indian J Dermatol Venereol Leprol 2020;86:115-23
| Introduction|| |
Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae). It is thought to be transmitted by droplets from untreated patients with a high bacillary load to susceptible individuals., Owing to the high risk of transmission, all contacts of an “active case” are potential “future cases” which may further give rise to new cases exponentially. The management of contacts of leprosy cases is therefore a priority.
The implementation of multidrug therapy (MDT) has resulted in the reduction of leprosy prevalence globally. However, despite the free availability and effective utilization of MDT worldwide, the decline in newly detected cases over the past 10 years has been slow; from 249,007 cases in 2008 to 210,671 cases in 2017. The current global annual new case detection rate (ANCDR) is 2.7/100,000 population, marginally lower than in previous years. India, Brazil, and Indonesia contributed to 80.2% of the global new case load in 2017. The gradual decrease in ANCDR is not an unexpected phenomenon for a chronic infectious disease such as leprosy with long and unpredictable incubation period. The implementation of “leprosy case detection campaigns” as national programs in some countries facilitating detection of new cases may also be partly responsible for the relatively stagnant statistical data in recent years.
In 2012, the World Health Organization (WHO) set “roadmap targets” to reduce the global impact of 17 neglected tropical diseases including leprosy. A target for the “global interruption of transmission of leprosy by 2020” was set with the aim of bringing down the number of incident new cases from existing cases and, in the long run, eradication of leprosy. “Breaking the chain of transmission” as a leprosy control strategy has now gained momentum around the world. This not only includes early diagnosis and treatment but also treatment of the contacts of new cases who could harbor subclinical infection with the potential to later develop manifest disease. However, many challenges need to be overcome to reach this goal including optimal contact-tracing, confirmation of subclinical infections by appropriate diagnostic tests, establishment of an effective chemoprophylactic regimen, and large scale implementation of these regimens in leprosy-endemic countries.
| Contacts of a “case of Leprosy”|| |
Susceptibility to develop leprosy
An individual who is in prolonged association (≥20 h/week) with an index case of leprosy is considered to be a “contact.” Following exposure to an untreated case, only 5%–20% of the contacts may develop clinical features of leprosy.
Several factors determine susceptibility to leprosy [Table 1].,,,,, Although the bacillary load of the index case is the foremost factor determining the risk of disease transmission, contacts of paucibacillary (PB) index cases are also at risk. In a series of children with leprosy, Jain et al. recorded 38% PB contacts in the household and neighborhood. Contacts harbouring M. leprae may remain asymptomatic for long periods before they develop active disease. The risk of acquiring leprosy for different categories of contacts are presented in [Table 2].,,,,,
| Contact Tracing and Management|| |
Household contacts are often more amenable to antileprosy interventions such as clinical examination and prophylactic therapy. The “new-case detection campaigns” and “contact tracing programs” that are operative in some endemic countries aim to detect and treat yet unidentified cases to reduce the source of infection. Contacts of these new cases can be targeted with chemoprophylaxis to break the “chain of transmission”. Chemoprophylaxis can be administered either to individual high-risk contacts, or as a blanket intervention of the entire population around a newly detected case.
| Chemoprophylaxis|| |
Chemoprophylaxis is the “administration of drugs, including antibiotics, to prevent the development or progression of an infection to active manifest disease.” Preventing the entry of M. leprae into a new host is impractical, but chemoprophylaxis may abort the progression of disease in contacts who have acquired the organism. Hence, chemoprophylaxis in leprosy is aptly termed as post-exposure prophylaxis (PEP).
Trials on chemoprophylaxis of leprosy
Dapsone and acedapsone
The prophylactic value of dapsone in treating contacts of leprosy cases was first reported by Dharmendra (1965) from India. Several randomized controlled trials (RCT) describing dapsone as an effective chemoprophylactic agent soon followed,,, with efficacy rates varying from 34% to 99%.,,,, Lower efficacy rates of 28%–46% were reported from other endemic countries such as Korea, Uganda, and Philippines. Dayal and Bharadwaj reported an 86% efficacy rate of dapsone chemoprophylaxis in high-risk childhood contacts. Acedapsone was also studied in childhood contacts of lepromatous and smear-positive leprosy patients with efficacy rates of 44%–54%.,,,
Various drawbacks of dapsone chemoprophylaxis has limited its use for this purpose [Box 1].,,,
Rifampicin is bactericidal and a single dose kills up to 92.1% of M. leprae rendering the patient nearly noninfectious. In the first trial of rifampicin chemoprophylaxis among contacts of leprosy patients in southern Marquesas, a single dose of rifampicin (25 mg/kg) was observed to have a protective effect of 40%–50% at the 4th and 10th years., An Indonesian trial with two doses of rifampicin at 3.5 months intervals showed a protective effect of 75% at 3 years which was higher among distant contacts, as compared to household and neighbourhood contacts; this effect waned by 6 years to become nearly similar to the controls.,
In the landmark COLEP study conducted in two districts of north-west Bangladesh a single-dose of rifampicin (SDR) or placebo was administered to close contacts of newly diagnosed leprosy patients and followed up biannually for 4 years. The overall decrease in the incidence of leprosy at 2 years was 57%, but there was no significant difference between the groups at 4 years. As with the Indonesian trial, a greater protective effect on distant contacts (as compared to household contacts in whom the protective effect was <30%) was noted.M. leprae–specific anti-phenolic glycolipid-1 (anti-PGL-1) antibody negative contacts achieved higher protection as compared to seropositive cases.
With support from the Damien Foundation, Belgium, nine double-blind RCTs (SDR vs. placebo) were conducted in household contacts of leprosy cases in India., MDT was administered to new leprosy cases detected through “rapid village surveys (RVS)”. SDR was administered to the household contacts of these patients 2–3 months after the initiation of MDT in the index case and followed annually. An incidence of 2.3 new cases/10,000 person-years was seen in the SDR group as compared to 8.7 in the placebo group at the end of 4-5 years (risk reduction 74%).
Based on the results of the Indonesian and COLEP studies, the “Leprosy Post-Exposure Prophylaxis Program” (LPEP) was launched in 8 countries (Tanzania, India, Nepal, Sri Lanka, Myanmar, Indonesia, Brazil, and Cambodia) in 2014 under the mutual partnership of the Ministries of Health of the respective countries, the members of the “International Federation of Anti-Leprosy Associations (ILEP),” and the Novartis Foundation. The objective of this project was to study the impact of SDR in preventing transmission of leprosy and to identify effective ways to integrate chemoprophylaxis into routine leprosy control programs in endemic areas. In each country 1-3 districts were selected for implementation of LPEP. SDR-PEP was administered to the subclinical contacts of the index cases.
National LPEP project guidelines have been set in India, Nepal, and Indonesia. Preliminary reports show not only a high acceptance of SDR-PEP among contacts but also that it is feasible to incorporate this into existing leprosy control programs.
Pitfalls of SDR chemoprophylaxis as evidenced in the COLEP trial are presented in [Box 2].
Trials on multidrug chemoprophylactic regimen
Various drug combinations have been used to formulate a highly bactericidal chemoprophylactic regimen with a longer-lasting protective effect.,, Placebo-controlled trials with ROM therapy (single dose rifampicin 600 mg, ofloxacin 400 mg, and minocycline 100 mg) have not demonstrated superiority over SDR. The disadvantages of ROM chemoprophylaxis are presented in [Box 3].,
Newer antileprosy drugs as chemoprophylactic agents
An ideal antibiotic for chemoprophylaxis must have certain properties [Box 4].
Several second-generation antileprosy drugs are highly bactericidal against M. leprae in animal and human studies including the ansamycins (rifapentine, rifabutin), fluoroquinolones (moxifloxacin, ofloxacin, pefloxacin), macrolides (clarithromycin), and tetracyclines (minocycline). New antileprosy regimens using these drugs have been studied extensively and experience gathered from their use in the treatment of leprosy can be applied to make use of these as chemoprophylactic agents. [Table 3],, However, implementation of these regimens on a large scale is limited by high cost, increased risk of adverse drug reactions and other technical factors. Some studies have also shown that regimens using second-line antileprosy drugs are either not beneficial or only marginally superior to the existing WHO-MDT even in rifampicin-resistant cases.,,
|Table 3: Few regimens using new drugs trialed in the treatment of leprosy,,,|
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Prospects of new drugs as chemoprophylactic agents
The relative merits of these second-generation antileprosy drugs as chemoprophylactic agents over rifampicin are presented in [Table 4].,,,,,,,
|Table 4: Prospects of new drugs as chemoprophylactic agents with advantages and disadvantages over rifampicin,,,,,,,|
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Although rifampicin resistance has been documented, it is thought that the possibility of rifampicin resistance arising in patients with subclinical leprosy is very low as they are estimated to harbor fewer than 10M. leprae in total or <10 viable M. leprae., Based on this assumption as well as the confidence arising from its long use both as a chemotherapeutic and chemoprophylactic agent, rifampicin still remains the drug of choice for leprosy chemoprophylaxis.
Various limitations of chemoprophylaxis and the stigma associated with implementation have been discussed in [Box 5].,,
| Combined Chemoprophylaxis and Immunoprophylaxis|| |
The protective effect of BCG vaccine against leprosy is based on antigen sharing between M. tuberculosis and M. leprae. There is ample evidence of the protective effect of BCG vaccine in leprosy prevention. A meta-analysis of evidence drawn from seven experimental studies showed a protective effect of 26%, whereas an overestimated value of 61% was obtained from 19 observational studies. In another meta-analysis (excluding observational studies), 78.3% of the 29 studies showed significant protective effect. In trials, cohort studies, and case–control studies statistically significant protective effects of 43%, 62%, and 59% were seen respectively.
Role of neonatal BGG vaccination in prevention of transmission of leprosy
In most parts of the world, mandatory BCG vaccination at birth is part of “Expanded Programme of Immunization (EPI, WHO)”.
Protective effects of BCG vaccination in leprosy are discussed in [Box 6].,,
Chemoprophylaxis among contacts having neonatal BCG vaccination
Individually, SDR and neonatal BCG vaccination each may provide around 60% protection against transmission of M. leprae to household contacts, but when an already BCG-vaccinated contact receives SDR, the protective effect increases to about 80%.,,, However, as with SDR prophylaxis, greater benefits accrue to contacts of PB cases and for distant contacts. Both SDR chemoprophylaxis and BCG vaccination individually do not optimally protect the close contacts of MB and smear-positive index cases.
Role of BCG revaccination in prevention of transmission of leprosy
The COLEP study showed that BCG immunoprophylaxis potentiated the protective effect of chemoprophylaxis. A cluster RCT to compare the effect of BCG immunoprophylaxis alone with a combination of BCG immunoprophylaxis and SDR chemoprophylaxis among contacts of newly diagnosed leprosy patients (MALTALEP study, Bangladesh) is ongoing.
In a study from Brazil, 56% protective effect of BCG vaccination has been demonstrated in contacts of patients with leprosy irrespective of their neonatal vaccination status. Based on this, BCG revaccination to leprosy contacts has been adopted as a government policy in that country.,, Another study from Malawi found that a second dose BCG vaccine conferred 50% protection against leprosy. However, the role of BCG revaccination later in life is debatable.,,
The immunoprophylactic effects of four vaccines, BCG, BCG + killed M. leprae, Mycobacterium w (Mw), and ICRC, were evaluated in double-blind RCT conducted in South India.Mw showed the lowest protective effect of 25.7% while that of BCG, ICRC and BCG + killed M. leprae were 34.1%, 65.5% and 64% respectively., The authors concluded that the ICRC and BCG + killed M. leprae vaccines had potential for prevention of leprosy. There was no evidence of beneficial effect of additional dose of BCG vaccination during first year, but statistically significant higher value was recorded during follow up.,
In a cluster-randomized community trial (BCG-REVAC), a large cohort of normal Brazilian school children were administered an additional dose of BCG vaccine to assess its impact in prevention of transmission of both tuberculosis and leprosy. At 6 years 8 months, there was no difference in the occurrence of new leprosy cases among the revaccinated and non-revaccinated groups.
Thus, revaccination of household contacts with BCG does not appear to be a viable strategy in prevention of leprosy. However, neonatal BCG vaccination as part of EPI must be made compulsory in leprosy-endemic countries. BCG vaccination at birth may be encouraged through special campaigns, especially in the states with high endemicity for leprosy and in the families with sufferers of leprosy. During active or passive surveillance for new leprosy cases, screening for a BCG scar must be made mandatory and if a new case or a household contact lacks a BCG scar, vaccination should be carried out immediately. It must be emphasized that concomitant administration of vaccine at a later date and chemoprophylaxis is contraindicated; if chemoprophylaxis is given first, then BCG administration should be deferred by at least 24 hours, while if BCG is administered first then chemoprophylaxis should be delayed by 1 month. This involves two visits by health workers thereby increases costs.
BCG vaccination may increase the risk of occurrence of leprosy
Duppre et al. from Brazil noted a higher incidence of tuberculoid leprosy in the contacts without neonatal BCG, during earlier months of the first year of vaccination at a later date., However, this risk reduced after the first year and this group of contacts subsequently achieved a protection of 80%.,,,,, This observation has not been substantiated further, and one of the objectives of MALTALEP study is to reevaluate this finding.
MIP vaccine used for immunoprophylaxis
The immunoprophylactic effect of Mycobacterium indicus pranii (MIP or Mw vaccine) in contacts of leprosy patients is presented in [Table 5].,,, The results of these studies may be reevaluated for large scale applicability of this vaccine as an immunoprophylactic agent.
| Screening of Contacts to Detect Susceptibility to Leprosy|| |
There is no way of detecting susceptibility to leprosy in close contacts in order to use targetted chemoprophylaxis. Demonstration of anti-PGL-1 antibodies (IgM and IgG) among healthy contacts has shown a consistent association with future development of the disease with the risk being three times greater in seropositive individuals. However, the selection of cases for chemoprophylaxis on a large-scale based on this test does not appear practical [Box 7].
Rapid lateral flow assays (LFA) to detect M. leprae–specific antibodies are under trial in endemic countries for utilization in a field setup (gold-LFA and UCP-LFA). Both tests correspond to the bacillary index (BI) of the patients and the quantitative UCP-LFA has a higher sensitivity (94% vs.78%). The UCP-LFA is more sensitive than PGL-1 ELISA test but patients with a lower BI may not be detectable by either of these methods. The UCP-LFA format detects both humoral and cellular markers of M. leprae infection and is effective in detecting PB cases;, it was found efficacious in trials conducted in Bangladesh and other countries in Asia, Africa, and South America.
| Future Directions in Prevention of Transmission of Leprosy in High Endemic Countries|| |
SIMCOLEP is a micro-simulation model developed to study the transmission and impact of control measures of leprosy among the members of a household with an index case.,, The two components of the model are the “life history of individual family members” and the “natural course of infection with M. leprae” and it takes into account the formation, dissolution, and change of the households, transmission of leprosy between existing and new households, and evaluation of the interventions aimed at these household members. The SIMCOLEP study design was based on the data generated from the COLEP study and the trial was conducted in the same geographical area with the aim to compare the efficacy and future outcome of various leprosy intervention programs.,
At present, the global distribution of leprosy is uneven and cases are aggregated in three countries i.e. India, Brazil, and Indonesia. Although elimination has been achieved at the national level in both India and Indonesia, there are some high endemic states/areas contributing significantly to the disease burden in these countries as well as globally. This may be a hindrance in achieving the goal of “global interruption of transmission of leprosy by 2020 (WHO).” Blok et al. have used the SIMCOLEP model to predict the trend of incidence of leprosy in the high endemic regions of these three countries until 2030., With the existing leprosy control strategies in these countries, a downward trend in the ANCDR has been predicted by the year 2030; hence, it may be possible to achieve the goal of interruption of transmission at national level by 2020 as per the target set by the WHO. However, it would not be possible to achieve this goal in some thickly populated high endemic regions of these countries. To address this issue, enhanced control measures are required for these regions.
Future directions of chemoprophylaxis: The PEP++ regimen
The Netherlands Leprosy Relief proposed an enhanced chemoprophylaxis regimen (PEP++) with the aim of reducing leprosy transmission by 80%–90% from the existing 60%. A series of meetings were held with experts from all domains of leprosy control across the world. The criteria for choosing an optimal enhanced PEP regimen were set up: effective, safe, acceptable, available, affordable, feasible, and minimal chance of development of drug resistance. The expert committee concluded that the tentative PEP++ regimen should consist of 3 doses each of rifampicin (600 mg, weight-adjusted dose in children) and moxifloxacin (400 mg) at 4 weekly intervals (days 1, 29, and 57). In cases where moxifloxacin was contraindicated, clarithromycin (300 mg, weight-adjusted dose in children) could be used.
Two most bactericidal drugs (rifampicin and moxifloxacin) with longer half life and desirable pharmacodynamics were selected, the rationale being to enhance the protective effect with repeated doses and lowering the risk of inducing resistance. These two drugs are easily available, affordable, and with monthly dosage schedule, supervised administration is possible. The efficacy of the proposed PEP++ regimen is to be tested against SDR in cluster-randomized trials in close contacts of leprosy cases in high endemic regions of India, Brazil, and Indonesia.
However, through a recent circular (EMA/668915/2018, 5th October, 2018) the Pharmacovigilance Risk Assessment Committee (PRAC)” of the European Medicine Agency (EMA) has imposed restrictions on oral, parenteral, and inhalational use of quinolone antibiotics because of their rare but potentially long-lasting side effects on musculoskeletal and nervous systems. This has evoked a discussion regarding the use of moxifloxacin as the second drug in the PEP++ regimen on a large scale for healthy contacts of patients with leprosy. Taking account of this recommendation, the best PEP++ regimen for adults would be rifampicin (600 mg) in combination with clarithromycin (500 mg or 1000 mg).
Ongoing trials of a tetravalent subunit vaccine LepVax (89 kD chimeric fusion protein containing three prioritized antigens, ML2055, ML2380, ML2028, and additional ML2531, formulated in a toll-like receptor 4 ligand glucopyranosyl lipid adjuvant in stable emulsion (GLA se) in post-exposure experimental animals have shown an 85% reduction in M. leprae load at 12 months after vaccination. LepVax has a good safety profile besides having protective effects on cutaneous nerves and delays M. leprae–induced impairment of motor nerve function. In BCG-vaccinated animal models the antigen-specific responses to LepVax remain unaltered. All these characteristics favor its future use as an ideal immunoprophylactic agent.
| Conclusion|| |
Thirteen countries with ongoing leprosy transmission have signed the declaration “towards a world free of leprosy (Bangkok Declaration, 2013, WHO)., Despite the use of dapsone chemoprophylaxis to prevent transmission of leprosy five decades ago, the search for an ideal chemoprophylaxis regimen continues.
Implementation of any leprosy control program in endemic countries is a challenge to policymakers in terms of funds, manpower, and the difficulty of reaching geographical areas with pockets of leprosy. This economic burden could be reduced if blanket intervention could be replaced with chemoprophylaxis specifically targeted to subclinical cases identified by simple, highly sensitive laboratory tests.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]