Dear Pieter and colleagues,
In the 1980s victory had been declared against TB. There was a predictable exodus of talent and funding. Unfortunately, the real battle barely had started. How did the world of TB recover from that premature declaration of victory? Dr. Kochi, newly at WHO HQ, scoured the world for examples of highly successful field programmes. He found them in Dr. Styblo's programme in Tanzania and the success in New York City, both of which relied on earlier trials in India. The global situation soon was transformed partly because we (Dr. Kochi's small 1990s team at WHO) were grateful to learn from highly effective field programmes. On that basis we defined and promoted the DOTS strategy. It has since saved tens of millions of lives globally. As a result, the global TB budget has gone from only 100 million per year to several billions per year (although drug-resistant TB, latent TB and other challenges stand in the way of elimination). TB was once invisible, because dead persons are invisible. We made it highly visible. TB work has since become a magnet for young talent and reliable funding. Dr. Kochi, having transformed the situation in TB, then went on to start a transformation in malaria. That, again, was based on identifying measurable successes at the front-lines.
Given the circumstances, it seems wise to pay close attention to highly successful field programmes in HD (leprosy) too. Previous contributions here have noted the measurable successes in Uele (DR Congo) and Weifang/Shandong (China). There the incidence rate of MB HD was reduced rapidly. This is in stark contrast to the decades-long stagnation in the number of newly reported MB HD cases globally, or the unexpected increase in HD following some interventions. It seems wise to let the world know that HD is still an important problem because of a steadily accumulating burden of sequelae, but that some highly successful field programmes have already reduced transmission to near-zero levels. Such a combination of facts tends to be persuasive.
Another example of a successful field programme is reviewed and analysed below. It comes from a low-income population in India.
Regards,
Joel Almeida
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Karigiri, India: how transmission of HD (leprosy) rapidly was reduced in a low-income population
Abstract
A population-based HD control programme was launched in a low-income and extremely hyper-endemic area of India in 1962. Prolonged anti-microbial protection for all LL patients was ensured until about 1990, with treatment until smear negativity. A 16%/year decline is demonstrable in the incidence rate of LL (lepromatous) HD leading to near-zero transmission by the early 1990s.
However, the decline was then interrupted. New LL HD patients were taken off anti-microbial protection within 2 years and later only 1 year. This "fixed duration" treatment for even genetically anergic LLp HD patients was followed by an apparent resurgence in transmission of HD within a few years.
Prolonged anti-microbial protection for all LL HD patients is apparently necessary and sufficient to achieve a rapid decline in the incidence rate of LL HD, leading to near-zero transmission. It is useful also in protecting previously treated LL HD individuals from re-infection in endemic areas, and from the ravages of the bacilli. Prolonged anti-microbial protection for all LL HD patients also is the only proven method, so far, for rapid reduction in transmission capable of sustained near-zero transmission. It works powerfully even in poor hyper-endemic areas located near the equator.
It would be good to make prolonged anti-microbial protection widely available and free of charge for every known LL HD patient, as part of competent case management.
Introduction
The area reviewed and analysed here is the Gudiyatham Taluk administrative sub-district located in Tamil Nadu state of India, at 13 degrees N latitude. It is the HD control area of the Schieffelin Centre (SC), Karigiri with a population of over 400,000. By current criteria the area was originally extremely hyper-endemic, with newly detected MB HD patients alone reaching as high as 900/million population in the early 1960s. It includes substantial swathes of arid land. Most of the population survives by agricultural labour and tending of livestock (mainly cows and goats). Only a small minority of the population is employed by industries, a few of which export textiles and other finished goods to affluent countries. Nevertheless, it long remained a low-income area. Even as recently as 2003 its GDP per capita was only USD300 (less than one USD per person per day).
The Schieffelin Centre (SC) in Karigiri, India, was founded in this sub-district in 1955 at a time of intense widespread fear of persons affected by HD. The sulfones had only recently, in the words of Dr. Robert Cochrane, "torn the mask of terror from the face of leprosy". Nodular LL (lepromatous) HD and advanced disfigurements caused by HD were then relatively frequent. Patients initially self-reported to the centre for services. Mobile teams then took services to villages, as described below. Segregation formed no part of the approach. The Centre now offers a wide range of health services and programmes. It is renowned for being a pioneer and centre of excellence in HD control, research, reconstructive surgery, rehabilitation and training, among other achievements.
Population-based control programme
In 1962 the SC launched a population-based field programme to control HD. The methods and approaches have been summarised previously. (1) In short, mobile multi-skilled teams visited 44 villages at monthly intervals. Active case finding was carried out systematically, including population surveys, contact tracing and school surveys. Case management was delivered near the patients' homes. Tertiary care was available at the SC base hospital. Patients were known to hitch rides to the base with the mobile teams when required. Laboratory investigations, including histopathology, were used consistently. Good case management was the rule throughout each patient's lifetime.
Anti-microbial chemotherapy
Anti-microbial regimens have been described previously. (2) In short, until the early 1980s long-term dapsone was used. In the early 1980s MDT was introduced. LL patients (among others) previously on dapsone were switched to MDT, newly diagnosed LL patients (among others) were put on MDT, and treatment was continued until smear negativity. From the late 1980s onwards newly diagnosed LL patients were given fixed-duration MDT lasting 2 years. Eventually fixed duration MDT was shortened to 1 year, even for LL patients..
Results
Outcomes were reported by Norman et al (1) and are reviewed and analysed below.
Fig 1.
The incidence rate of LL HD declined rapidly. This decline continued uninterruptedly until the mid-1990s. A near-zero case detection rate for LL HD was achieved by then, as confirmed by an intensive case-finding programme. The average age at detection among all HD cases rose from about 23 years to about 31 years, owing in large part to a decline in the proportion of children among newly detected cases.
Fig. 2
The earlier favourable trends apparently changed with the introduction of fixed-duration treatment from the late 1980s. In the subsequent decade, the number of new LL HD patients started increasing. This was after the incidence rate of LL HD had declined to near-zero levels.
Discussion
The abandonment of prolonged anti-microbial protection in favour of fixed duration protection for even LL HD patients stopped the earlier decline in the incidence rate of LL and MB HD.
Fig. 3 Annually reported new MB patients globally, 1985 - 2019. (WHO WERs)
At global level, the annual number of newly reported MB patients has been stagnating in recent decades (Fig. 3). This contrasts with the rapid decline in new LL and MB HD patients achieved in Karigiri (Fig 2) and Uele/DRCongo (3). The decline in those successful field programmes continued as long as prolonged anti-microbial protection was ensured for LL HD patients (among others). When fixed duration treatment replaced prolonged protection, the earlier decline was lost. It is useful to understand why.
Fig. 4
Unprotected persons with LLp HD genomes are the only known source of astronomical numbers of highly concentrated viable bacilli in this area..(4) Armadillos do not occur naturally in India.
Fig. 5
Persons with LLp (polar LL) genomes have low ID50s for HD bacilli and easily can be infected or re-infected in endemic areas. Recurrence of LL HD is very difficult to diagnose promptly, because anergic patients tend to show few or no signs of bacillary multiplication for several years.
Fig. 6
Bacillary multiplication after 2 years of MDT is demonstrably frequent among patients with an initial BI > 4+, although usually manifested only 5 years or more after withdrawal of anti-microbial treatment. (5) Unprotected polar LL HD patients with recurrence are forced to entertain viable bacilli, despite having anergy and consequently being able to produce and shed astronomical numbers of highly concentrated viable bacilli. (4) All this harms the LL HD patients and is unhelpful to the population.
Fig. 7 Case detection rates in 2 prefectures of China over time. Upper line is Wenshan/Yunnan, lower line is Weifang/Shandong. Predominantly dapsone was used in both places before 1986
The nearest we have to a population-randomised controlled trial of prolonged MDT vs fixed duration MDT comes from China. Weifang/Shandong ensured prolonged MDT with support from the Sasakawa Health Foundation. By contrast, Wenshan/Yunnan in those same years apparently was constrained to use fixed duration MDT. The outcomes were well monitored and reported. (6) Prolonged MDT introduced in Weifang/Shandong accelerated the decline to about 20%/year (lower line, Fig. 7). Transmission rapidly was reduced to near-zero levels.(6) By contrast, fixed duration MDT in Wenshan/Yunnan (upper line, Fig 7) was followed by stagnation in the incidence rate of HD. This stagnation occurred despite the earlier decline with prolonged dapsone in an era of even lower income. In 2017, Shandong reported only 13 new HD patients from a population of about 100 million persons, down from about 40 in 2007.(7) The bulk of the reduction in transmission was achieved with prolonged anti-microbial protection for all LL HD patients while income in even Shandong was still low.
Prolonged anti-microbial protection for all LL HD patients is apparently necessary and sufficient to achieve a rapid decline in the incidence rate of LL HD. If sustained, it leads fairly rapidly to near-zero transmission. It is also useful in protecting previously treated persons with LL HD from re-infection, and from the ravages of the bacilli. Prolonged anti-microbial protection for LL HD patients (ever diagnosed) is the only proven method so far for rapid reduction in transmission leading to near-zero transmission. It works powerfully even in hyper-endemic areas with a very low income. It works even near the equator.
The Karigiri success parallels comparable successes in Uele (DR Congo, 3) and Weifang/Shandong (China, 6). The invariant element in all these successes appears to be prolonged anti-microbial protection for LL HD patients. This insight allows the devising of highly successful programmes.
Prolonged anti-microbial protection for LL HD patients could be achieved by:
a) continuation of MDT till smear negativity in patients with a high initial BI, or
b) monthly doses of 3 bactericidal drugs for patients with a high initial BI after the end of MDT (as already practised in India by some academic centres of excellence and private practitioners).
The costs of monthly doses of 3 bactericidal drugs after MDT for all LL patients is relatively modest even when summed across the globe (9). The epidemiological impact is likely to be decisive, with rapid reduction in the incidence rate of MB HD that is sustained with near-zero risk of selecting drug-resistant mutants. In this respect it is vastly more effective than the repeated "blanket" administration of a single dose of 3 bactericidal drugs used in the Federated States of Micronesia in the 1990s. (10) That had only temporary impact. Incidence rates returned to pre-intervention levels within a few years, probably because undiagnosed LL patients were missed during implementation. It is difficult for field workers to diagnose the often subtle signs of LL HD.
It would be good to make prolonged anti-microbial protection widely available and free of charge for every known LL HD patient, as part of competent case management. Neglect of previously treated LL HD patients often extends beyond just inadequate anti-microbial protection. For example, adjacent to this area of India where even non-diseased people are desperately poor, previously treated persons affected by HD were found to be destitute, homeless, forced to rely on alms for survival, and too frequently smear positive.(8) Such neglect is usually unintentional and careless, but damaging nonetheless. This neglect, including anti-microbial neglect, seems contrary to article 25.1 of the Universal Declaration of Human Rights. It is bad for the affected persons and bad for the population.
HD is an important cause of extreme poverty. Therefore ending the transmission of HD would help end extreme poverty. It also would reduce avoidable suffering among the affected individuals while protecting the already low-income population from a potentially devastating and often impoverishing disease. This contributes to both Universal Health Care and the Sustainable Development Goals.
It does not seem wise or even ethical to leave persons with polar LL genomes and anergy unprotected against these damaging bacilli, in endemic areas. Health care can be universal only if it includes this important group of people. The people of endemic countries, and the whole world, would love us to succeed at ending transmission, especially by showing respect for the inherent dignity of these human beings. We have examples of real success. This is indicated by rapid reduction in the incidence rate of new MB HD patients and even near-zero transmission. Let's make this happen everywhere.
Summary in translations
ध्रुवीय एलएल कुष्ठ रोग वाले व्यक्तियों को लंबे समय तक एंटी-माइक्रोबियल सुरक्षा की आवश्यकता होती है। यह तब तक एमडीटी हो सकता है जब तक स्मीयर नकारात्मक हो जाते हैं, या 3 जीवाणुनाशक दवाओं की मासिक खुराक। इसके बिना कुष्ठ रोग का संचरण जारी रहेगा और ध्रुवीय एलएल रोगियों को नुकसान होगा।
Pessoas com hanseníase virchowiana polar requerem proteção antimicrobiana prolongada contra recorrência. Isso pode ser PQT até que a baciloscopia torne-se negativa, ou doses mensais de 3 drogas bactericidas. Sem isso, os pacientes com hanseníase virchowiana polar sofrerão e a transmissão da hanseníase continuará, apesar de todos os outros esforços.
Orang dengan kusta LL kutub membutuhkan perlindungan anti-mikroba yang berkepanjangan terhadap kekambuhan. Ini bisa menjadi MDT sampai basiloskopi menjadi negatif, atau dosis obat bakterisida 3 bulanan. Tanpa ini, penderita kusta LL kutub akan menderita dan penularan akan terus berlanjut meskipun ada intervensi lain.
Les personnes atteintes de hanséniase polaire lépromateuse ont besoin d'une protection antimicrobienne prolongée contre les récidives. Cela peut être une PCT jusqu'à ce que les frottis deviennent négatifs, ou des doses mensuelles de 3 médicaments bactéricides. Sans cela, les patients atteints de hanséniase lépromateuse polaire en souffriront et la transmission de la lèpre se poursuivra, malgré tous les autres efforts.
Las personas con hanseniasis virchowiana polar requieren protección antimicrobiana prolongada contra la recurrencia. Puede ser PQT hasta que la baciloscopia sea negativa o dosis mensuales de 3 fármacos bactericidas. Sin esto, los pacientes con hanseniasis virchowiana polar sufrirán y la transmisión de la hanseniasis continuará a pesar de todos los demás esfuerzos.
極性ハンセン病の人は、再発に対する長期的な抗菌保護が必要です。これは、細菌検査が陰性になるまで、MDTの延長、または3つの殺菌剤の月用量である可能性があります。これがなければ、極性ハンセン病の患者は苦しみ、他のすべての努力にもかかわらず、ハンセン病は広がり続けるでしょう。
References
1. 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.
2. Norman G, Joseph G, Richard J. 2004. Relapses in multibacillary patients treated with multi-drug therapy until smear negativity: findings after twenty years. Int J. Leprosy 72:1–7
3. Tonglet R, Pattyn SR, Nsansi BN et al. The reduction of the leprosy endemicity in northeastern Zaire 1975/1989 J.Eur J Epidemiol. 1990 Dec;6(4):404-6 reviewed in: 5a. Almeida J. Reducing transmission in poor hyperendemic areas - evidence from Uele (DRC). LML 29 Nov 2019
4. Davey TF, Rees RJ. The nasal dicharge in leprosy: clinical and bacteriological aspects. Lepr Rev. 1974 Jun;45(2):121-34.
5. Balagon MF, Cellona RV, dela Cruz E et al. Long-Term Relapse Risk of Multibacillary Leprosy after Completion of 2 Years of Multiple Drug Therapy (WHO-MDT) in Cebu, Philippines. American Journal of Tropical Medicine and Hygiene, 2009; 81, 5: 895-9. reviewed and analysed further in 4a. Almeida J Recurrence rate among MB patients following RFT. LML 2 June 2019.
6. 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 & analysed further in: 7a. Almeida J. What really happened in Shandong? LML 16 Nov 2019
7. Chu T, Liu D, Huai P et al. Comprehensive measures succeeded in improving early detection of leprosy cases in post-elimination era: Experience from Shandong province, China. PLoS Negl Trop Dis. 2020 Feb; 14(2): e0007891
8. Rao PS, Mozhi NM, Thomas MV. Leprosy affected beggars as a hidden source for transmission of leprosy. Indian J Med Res. 2000 Aug;112:52-5.
9. Almeida J. Drug costs & impact of post-MDT chemoprophylaxis for LL patients. LML 9 July 2019
10. 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 Organi
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