Leprosy Mailing List – December 14, 2021
Ref.: (LML) Drug Resistance in Mycobacterium Leprae in the Context of Zero Leprosy
From: Joel Almeida, London and Mumbai
Dear Pieter & colleagues,
It seems helpful to learn from the most impactful projects in endemic countries. To take just one example, Karigiri (India) shows what can be achieved in even low-income areas by simply providing quality services, based on a good understanding of the facts (see LML 30 Oct 2020 for details). Quality care could become our mantra as we seek to free people from the damaging impact of HD (Hansen's Disease) and its sequelae. Not all efforts have been successful, but the successful projects have demonstrated a surprisingly rapid decline in incidence rate of MB (multibacillary) HD. We could emulate successful projects. This will allow us to produce great outcomes and impact in steadily more places.
Drug resistance could derail success, which is why it requires attention.
Best,
Joel Almeida
- - - -
Drug resistance and HD control
Drug resistance is important. It remains probably the single most important threat to controlling HD (Hansen's Disease). That is because drug resistance is almost impossible to reverse. Delaying drug resistance helps ensure that MDT remains effective and HD remains easily treatable. How can we ensure that?
1) Ensure full MDT for every highly bacillated person, not just a single drug and not just a few doses of treatment.
Such errors are most likely when inexpert health workers (or even overworked practitioners) examine a person with undiagnosed LL (lepromatous) HD, conclude that there are no patches therefore no HD, omit smear microscopy, and then offer a single dose of rifampicin. This dose of rifampicin kills over 90% of rifampicin susceptible bacilli and so increases the frequency of rifampicin-resistant mutants by 1000%. This is dangerous not only for the undiagnosed LL HD patient, but also for their contacts, because the nasal discharges from just one unprotected LL HD patient can contain as many as 10 million viable bacilli/day. Further, the undiagnosed LL HD patient might disregard eventual signs of HD on the basis of that single dose of rifampicin. But full MDT is required for LL HD patients, not a single dose of rifampicin..
That addresses the risks from single dose rifampicin. What about benefits? The Indonesian program stated, after implementing single dose rifampicin for several years "The number of new cases, the proportion of child cases in the intervention areas using the contact approach or community participation has not shown a declining trend." (emphasis added) In short, single dose rifampicin for contacts had little or no impact. This was in keeping with an early 2000s study carried out on a few Indonesian islands, comparing two rounds of mass rifampicin administration vs two rounds of contact rifampicin administration vs no prophylaxis.(1) Giving NO prophylaxis was about as effective/ineffective as giving two doses of rifampicin to contacts.
Despite its lack of epidemiological impact, a single dose of rifampicin will select rifampicin resistant bacilli in the undiagnosed LL HD patients unfortunate enough to receive it. This selection can remain concealed by the relative insensitivity of tests to detect drug-resistant mutants. Repeated doses of rifampicin would compound the selection of rifampicin-resistant mutant bacilli. People in endemic areas need to understand this, in order to protect their own best interests. Open sharing of relevant information can become the norm not just in affluent countries but also endemic countries. Drug-resistance is a heavy price to pay in exchange for near-zero benefit.
Brazil and other major endemic countries now protect their people against single dose rifampicin. MDT will retain its efficacy in such enlightened countries. Is there an alternative to using rifampicin on its own, and that too just among contacts? Mass multi-drug administration in high endemic hot spots (e.g., former HD "colonies") can produce good epidemiological impact without selecting drug resistant mutant bacilli.(see below)
2) Rifampicin resistance is already increasing rapidly in India
In 2017, rifampicin-resistant bacilli were detected in only 2% of patients with signs of recurrent HD, in an area of India. By 2020, this figure had risen to 12.3%.(2) Further, 5% of previously untreated patients in that area were demonstrated to have rifampicin-resistant mutants.(3) Interestingly, patients with rifampicin-resistant recurrence and new patients with rifampicin-resistant mutant bacilli were observed to live in close geographical proximity. This is consistent with transmission of rifampicin-resistant bacilli.
Previously, a Brazilian total-population survey of a high endemic area showed that over 40% of patients with signs of recurrent disease had mutant bacilli simultaneously resistant to rifampicin and dapsone.(4) Rifampicin resistance is not just in the future, it is in the present.
3) Precautions against drug-resistance
Monitoring drug resistance is helpful, especially as the sensitivity of tests improves. However, monitoring by itself it cannot stop the selection of drug resistant mutants. Effective action would be good..
a) Use multiple drug combinations always, instead of single drugs (never rifampicin on its own).For example, Rifampicin + Ofloxacin + Minocycline (ROM) was promoted by WHO, including for mass multi-drug administration in high endemic hot spots of FS Micronesia, alongside expert skin camps and MDT till smear negativity. That WHO intervention produced about 40%/year decline in newly detected HD cases..
(see LML 22 May 2021, 22 Nov 2020 & refs 5, 6)
b) Ensure that MDT in LL patients is prolonged sufficiently for all drug-resistant mutant bacilli to be killed.
Drug resistance has ruined the prospects of controlling several other diseases. Fortunately, a growing number of enlightened people and organisations are keen on delaying drug resistance in HD. That seems wise. Lessons from highly successful projects can be applied widely, so that drug resistance is delayed, MDT remains effective, HD remains easily treatable, and success can become widespread.
References
1. Bakker MI, Hatta M, Kwenang A et al. PREVENTION OF LEPROSY USING RIFAMPICIN AS CHEMOPROPHYLAXIS. Am. J. Trop. Med. Hyg., 72(4), 2005, 443–448.
2. Singh I, Lavania M, Ahuja M et al. A FOUR-YEAR RETROSPECTIVE STUDY SHOWS INCREASING RATES OF ANTIMICROBIAL DRUG RESISTANCE IN ENDEMIC REGION IN INDIA FOR M. LEPRAE. Abstracts of the 31st biennial conference of the Indian Association of Leprologists, Hyderabad, India. April 2021. pp. 96-97
3. Ahuja M, Lavania M, Sharma R et al. MOLECULAR SCREENING OF NEWLY DIAGNOSED LEPROSY CASES FOR DRUG RESISTANCE IN M.LEPRAE. Abstracts of the 31st biennial conference of the Indian Association of Leprologists, Hyderabad, India. April 2021. p. 97
4. Rosa PS, D'Espindula HRS, Melo ACL et al. Emergence and transmission of drug/multidrug-resistant Mycobacterium leprae in a former leprosy colony in the Brazilian Amazon. Clinical Infectious Diseases. 1 July 2019, ciz570, https://doi.org/10.1093/cid/ciz570
5. WORKSHOP ON THE PREVENTION OF LEPROSY, POHNPEI, FEDERATED STATES OF MICRONESIA. 25-27 MAY 1999 sponsored by the Sasakawa Memorial Health Foundation Tokyo, Japan and the Western Pacific Regional Office of the World Health Organization. Int J Lepr, 67 (4) (SUPPLEMENT)
6. Diletto C, Blanc L, Levy L. Leprosy chemoprophylaxis in Micronesia. Lepr Rev. 2000;71(Suppl):S21–3
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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