Leprosy Mailing List – March 25, 2021
Ref.: (LML) Mass multi-drug administration circumvents the harmful effects of single drug use
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
Everyone wants to end transmission of HD (leprosy). Facts help.
Regards,
Joel Almeida
= = = = =
Mass multi-drug administration removes the harmful effects of single drug prophylaxis
The LPEP programme's self-declared intention was to evaluate "feasibility, effectiveness and impact" of PEP (post-exposure prophylaxis) with SDR (single dose rifampicin). The hope was to show a decreasing trend in the new case detection rate.(1) However, the effectiveness and impact of the LPEP programme have not been reported (2). This is a conspicuous omission. It suggests disappointing effectiveness and impact. Normally, outcomes are reported even if promoters find them disappointing.
Earlier, a demonstrable 16% to 20% annual decline in the new case detection rate had followed anti-microbial chemotherapy ingested regularly till smear negativity, even in areas characterised by low incomes at the time (3,4). Such declines followed prolonged dapsone or prolonged MDT for LL patients. Areas that withdrew MDT from anergic LL (polar LL) patients after 12 or 24 monthly doses fared less well. Transmission is common in those areas, across the globe, with only slow decline in new case detection rates. Previously treated, but since neglected, LL patients are susceptible to reinfection and are known to increase vastly the risk of HD among children in a household. (5) While the neglected LL patients themselves suffer an increased risk of painful ENL neuritis.(6) Also, in an endemic area with a well-run control programme, examination of household contacts yields only 8% to 16% of new HD cases.(7) All this helps explain why LPEP (SDR PEP) had disappointing effectiveness and impact. Leaving anergic LL patients unprotected against reinfection is a recipe for continuing transmission, and no amount of prophylaxis is likely to compensate.
The effectiveness and impact of SDR PEP might be disappointing, but is SDR PEP harmless? A randomised controlled trial compared an SDR (single dose rifampicin) group with a non-SDR (control) group among healthy contacts of HD ("leprosy") patients.(8) Contacts in both groups had received BCG (a cultivable mycobacterium) at least 8 weeks earlier. Outcomes were clinical signs of multibacillary (MB) HD and paucibacillary (PB) HD, respectively, at 1 and 2 years. By the second follow-up, 11 contacts in the rifampicin group showed MB HD compared to only three in the control group. The groups had roughly equal numbers. The entire groups formed the denominators for comparison, no sub-group analysis was involved (contrary to mistaken claims by some). Further, the excess of MB HD in the rifampicin group increased over time, between year one and two. The trial was cut short prematurely, but continuation would have highlighted further the growing excess of MB HD in the SDR group. The increased risk of MB HD is harmful, particularly since MB HD is 12 times more likely than PB HD to cause nerve function impairment, (9) often a precursor to permanent visible deformity. And a subset of MB patients, unlike PB patients, can be infectious if left unprotected against bacilli.
It seems humane to spare the people of endemic countries from interventions such as SDR PEP which have been known to increase the risk of MB disease. Ethical alternatives are available, as will be noted below.
Further, Article 12 of the Universal Declaration of Human Rights enshrines the right to privacy. People with HD are still (unnecessarily) feared and shunned. The LPEP (SDR PEP) programme, however, disclosed the private health information of newly diagnosed HD patients to neighbours (except in Brazil where the patient groups objected, vigorously defending privacy and confidentiality. The national programme of Brazil eventually stepped in to protect the Brazilian people against SDR PEP). Many newly diagnosed HD patients have low incomes and little schooling. Since the LPEP implementation ended, the "MALTALEP" RCT (8) cited above was published showing more MB HD cases arising in the SDR PEP group. Knowledgeable and affluent people might be able to defend themselves against such harmful interventions. But poor or illiterate people might not fully grasp the biological concepts and risks. They more easily succumb to "sales talk" that understates the potential impact on future marriage prospects, social prejudices, etc.
It seems fair to spare trusting people in endemic countries from interventions which gloss over adverse social and economic consequences. The Brazilian national programme protects all the people of Brazil, including those who are poor or illiterate. It sets a good example for endemic countries.
Anti-microbial resistance is important. The world's only total-population drug-resistance survey, so far, found that multiple-drug resistance already is frequent and frequently transmitted. (10) Drug resistance tends to convert easily treatable conditions steadily into hard-to-treat, disabling conditions. A single dose of rifampicin at 10 mg/kg reduced susceptible bacilli by over 90% in the mouse footpad test. (11) That implies a greater than ten-fold increase in the proportion of drug-resistant mutants among surviving bacilli. Mutation generally is spontaneous, not reliant on drugs. Drugs, including rifampicin, merely select pre-existing drug-resistant mutants. This is likely especially in undiagnosed "de novo" LL (lepromatous) HD patients who can harbour astronomical numbers of bacilli while showing only subtle physical signs. Most primary care workers are likely to misclassify such "covert" LL contacts as being free from HD. Giving undiagnosed persons with LL disease a single dose of rifampicin is a recipe for selecting drug-resistant mutants.
It seems humane to spare the people of endemic countries from interventions that select drug-resistant organisms. Selecting drug resistant bacilli is akin to polluting the community well from which everyone must drink. It is best avoided.
All these issues can be circumvented simply by using multi-drugs instead of a single drug for prophylaxis. Mass multi-drug administration involves offering multi-drug prophylaxis at intervals to the whole population of hyper-endemic zones, as was done temporarily in Micronesia.(12) There, integrated skin camps and MDT till smear negativity had accompanied mass multi-drug administration. The combination of rifampicin + ofloxacin + minocycline (ROM) was given in two rounds, with one year between the rounds. The outcome was a 92% decline in the risk of incident HD in those who received ROM in the first round, compared to those who did not. The number of newly diagnosed HD patients declined by over 90% within 2 years. The Sasakawa Health Foundation and WHO sponsored that highly impactful intervention. This intervention comes from the Asia-Pacific region, but that is not a good reason for disregarding it. It is an ethical and humane way of reducing transmission very rapidly.
Meanwhile, local professionals in endemic countries witness the disastrous effects of enforcing anti-microbial neglect of LL patients following 12 months of MDT: an accumulation of highly bacillated previously treated patients suffering painful ENL episodes, along with social and economic exclusion that treats them as sub-human. The patients need to be heard more, as do the noble-minded local professionals serving them.
Conclusion
Mass multi-drug administration, alongside integrated skin camps and MDT till smear negativity, so far is the world's most successful intervention against HD. 90% reduction of new HD cases within 2 years is demonstrably achievable. Repeating this every 6 to 9 months would cement the victory.
Endemic countries deserve the elbow room to succeed, without external pressure to adopt harmful interventions such as SDR PEP (LPEP). Instead, organisations in affluent countries could be more willing to learn from successes in endemic countries. The Brazilian national programme must be congratulated for taking a view. There is no substitute for the best local talent doing its best for its own people. (13)
References
1 Barth-Jaeggi T, Steinmann P, Mieras L LPEP study group, et al Leprosy Post-Exposure Prophylaxis (LPEP) programme: study protocol for evaluating the feasibility and impact on case detection rates of contact tracing and single dose rifampicin BMJ Open 2016;6:e013633. doi: 10.1136/bmjopen-2016-013633
2 Richardus JH, Tiwari A, Barth-Jaeggi T et al, Leprosy post-exposure prophylaxis with single-dose rifampicin (LPEP): an international feasibility programme. Lancet Global Health. Published online October 29, 2020 https://doi.org/10.1016/S2214-109X(20)30396-X
3 Li HY, Weng XM, Li T et al. Long-Term Effect of Leprosy Control in Two Prefectures of China, 1955-1993. Int J Lepr Other Mycobact Dis. 1995 Jun;63(2):213-221. Reviewed in LML 16 Nov 2019
4 Norman G, Bhushanam JDRS, Samuel P. Trends in leprosy over 50 years in Gudiyatham Taluk, Vellore, Tamil Nadu. Ind J Lepr 2006. 78(2): 167-185. Reviewed in LML 29 Oct 2020
5 Vijayakumaran P, Jesudasan K, Mozhi NM, Samuel JD. Does MDT arrest transmission of leprosy to household contacts? Int J Lep 1998; Jun;66(2):125-30. Reviewed in LML 31 Dec 2020
6 Balagon MVF, Gelber RH, Abalos RM, Cellona RV. Reactions following completion of 1 and 2 year multidrug therapy (MDT) Am J Trop Med Hyg 2010 Sep;83(3):637-44. doi: 10.4269/ajtmh.2010.09-0586. Reviewed in LML 7 Jan 2021
7 Butlin CR, NIcholls P, Bowers B. Outcome of late healthy household contact examinations in leprosy-affected households in Bangladesh. Lepr Rev (2019) 90, 305 – 320
8 Richardus R, Alam K, Kundu K, Chandra Roy J, Zafar T, Chowdhury AS, et al. Effectiveness of single-dose rifampicin after BCG vaccination to prevent leprosy in close contacts of patients with newly diagnosed leprosy: A cluster randomized controlled trial. Int J Infect Dis. 2019;88:65-72.
9 Croft RP, Nicholls PG, Steyerberg EW, Richardus JH, Withington SG, Smith WCS. A clinical prediction rule for nerve function impairment in leprosy patients-revisited after 5 years of follow-up. Lepr Rev 2003 Mar;74(1):35-41.
10 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
11 Almeida, JG. A quantitative basis for sustainable anti-Mycobacterium leprae chemotherapy in leprosy control programs. Int J Lepr (1992) 60(2):255-268.
12 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)
13 EDITORIAL Global health 2021: who tells the story? The Lancet Global Health VOLUME 9, ISSUE 2, E99, FEBRUARY 01, 2021 OI:https://doi.org/10.1016/S2214-109X(21)00004-8
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