Leprosy Mailing List – July 9, 2019
Ref.: (LML) Drug costs & impact of post-MDT chemoprophylaxis for LL patients
From: Joel Almeida, London and Mumbai
Dear Pieter,
The evidence indicates that recurrence of disease occurs in as many as 75% of LLp patients in an endemic area after even 24 months of MDT (1, 1a). These recurrences include endogenous relapse and exogenous re-infection. Signs of recurrence in these genetically predisposed patients are not easy to detect promptly. Nor is it easy to identify LLp patients without histopathology or reliable laboratory studies. Therefore, it seems wise to protect all LL patients with monthly post-MDT chemoprophylaxis (eg., rifampicin+moxifloxacin+minocycline).
The observed rate of decline in new cases following prolonged MDT for LL patients in Shandong was about 20%/year. This contrasted with the negligible decline following fixed duration MDT for LL patients in Yunnan. (2, 2a). Unlike Yunnan, Shandong largely prevented recurrences among LL patients. In so doing, it interrupted transmission at the main remaining source of concentrated viable bacilli. That proved necessary to end the disease.
We can provide monthly post-MDT chemoprophylaxis to all LL patients as a normal part of competent case management, to prevent recurrence of disease. In so doing, we can attempt to match Shandong's 20%/year rate of decline in new cases, ending in near-zero transmission.
Marginal cost of drugs
Monthly post-MDT chemoprophylaxis with rifampicin+moxifloxacin+minocycline currently costs about USD20 / treated person / year in the retail market. If we provide this to every new LL patient after MDT for an average of 10 years, and achieve Shandong's 20% rate of decline in new cases, then the number of new cases averted each year will be as shown in Figure 1.
Figure 1. Predicted number of new cases averted in each year after addition of monthly post-MDT chemoprophylaxis for every LL patient globally.
The marginal drug costs in each year would be as shown in Figure 2. This assumes 25% of all newly detected patients will show clinical signs (and/or skin smear BI) consistent with LL disease.
Figure 2. Predicted drug costs for providing 10 years of monthly post-MDT chemoprophylaxis to every new LL patient globally, in each year after its introduction.
Averting visible deformity and premature death
DALYs are disability-adjusted life years. In plain language, they are a summary measure of suffering/disability and premature death.
About a third or more of patients starting MDT eventually develop visible deformity under normal programme conditions, as indicated by a rural sample survey in India (3, 3a). The physical, psychological and social impacts of visible deformity are considerable, reducing the quality of life by an average of at least 20% and hastening eventual premature death. Assuming that the average age at onset of visible deformity is about 35 years, and using the standard 80-year life expectancy favoured by the Institute for Health Metrics and Evaluation, each affected person with visible deformity endures a 20% reduction in quality of life attributable to visible deformity over an average duration of 45 years. This amounts to 9 DALYs per person with visible deformity, even disregarding premature death. If premature death is taken into consideration, the DALYs per person with visible deformity are likely to exceed 9 and could be as high as 19 DALYs.
The future stream of DALYs averted in each year after introduction of monthly post-MDT chemoprophylaxis is shown in Figure 3.
Figure 3. Future DALYs averted in each year following the introduction of post-MDT chemoprophylaxis for LL patients globally. This estimate disregards eventual premature death attributable to disease sequelae and their consequences.
If we start monthly post-MDT chemoprophylaxis within the next year, we could achieve as much as a 90% reduction in annual new cases within a decade. We would also avert a stream of DALYs long into the future. By 2040 we will have averted roughly 3.2 million new cases, over 1 million new persons with visible deformity, and at least 9.6 million DALYs. This will be achieved at an average marginal drug cost for monthly post-MDT chemoprophylaxis of only USD 2.5 million/year globally. By 2040, in this scenario, there will be only about 600 new LL patients globally. They can be provided post-MDT chemoprophylaxis at a marginal drug cost of only about USD 12,000 / year. The endemic will be in terminal decline.
Accordingly, the marginal drug cost of post-MDT chemoprophylaxis for all LL patients is under 6 USD/DALY if premature death is disregarded, and under 3 USD/DALY if premature death is taken into consideration. This makes the intervention one of the world's most cost-effective against any disease. It is a strong "best buy" for the world.
More importantly, we will be saving human limbs, eyes, minds, relationships, educations and livelihoods from the unnecessary ravages of the bacilli. Those gains have intrinsic value. Further, when new cases start declining at the rate of 20% per year, the taxpayer bill for disability pensions will also start declining. Therefore, it is sensible to invest sufficiently. Post-MDT chemoprophylaxis is a key component of competent case management for LL patients, but there are other components including rehabilitation and inclusion services. Governments and NGOs can continue to keep boosting investment and improving comprehensive case management services for LL patients.
Consequences of delay
What are the predicted consequences of delaying the introduction of post-MDT chemoprophylaxis for LL patients? This is shown in Figures 4 and 5.
Figure 4. Predicted number of new cases globally over time according to year of introducing post-MDT chemoprophylaxis for all LL patients.
The cumulative excess of new cases is shown below in Figure 5.
Figure 5. Cumulative global excess of new cases attributable to delay in introducing post-MDT chemoprophylaxis for all LL patients.
If we delay for about 6 years, we could have about 1 million unnecessary new cases by 2030. That is equivalent roughly to the entire population of a good-sized city (eg., Chandigarh, Goiania, Mbuji-Mayi, Birmingham UK, San Jose USA, Adelaide, Amsterdam+Utrecht), or a fifth of the entire population of New Zealand. Imagine condemning every single person in San Jose or Birmingham unnecessarily to this potentially devastating disease, robbing a third of them of between 9 and 19 healthy years of life and incurring a huge taxpayer bill for disability pensions. It is unthinkable. If we delay for about 11 years, we could have as many as 2 million unnecessary new cases by about 2030. That is roughly the entire population of Sapporo (Japan) or Medan (Indonesia) or Brasilia. Instead, we can introduce monthly post-MDT chemoprophylaxis for all LL patients globally as a normal part of competent case management, and interrupt transmission as Shandong did.
Recurrence of disease and multiple drug-resistant bacilli
There is now another pressing reason for introducing monthly post-MDT chemoprophylaxis for LL patients. This is the high frequency of multiple drug-resistant bacilli in patients treated with fixed-duration MDT, revealed by the first-ever population-based survey (4). Recurrent disease among genetically predisposed individuals and drug-resistant bacilli set up a mutually reinforcing downward spiral, despite fixed-duration MDT, yielding a disease prevalence that once reached as high as 1282/10000 persons. Delay in introducing post-MDT chemoprophylaxis for all LL patients would unnecessarily keep the endemic alive. This would invite widespread drug-resistant disease globally, a catastrophe. We cannot afford to sleepwalk any more.
It is better for us to introduce post-MDT chemoprophylaxis for all new and known LL patients, urgently, as a normal part of competent case management. In so doing we will not only respect the human rights of LL patients and protect their nerves, but also hasten the end of the disease before multiple drug-resistance ruins our prospects.
Joel Almeida
Translations
एमडीटी के 24 महीने देने के बाद भी 75% "ध्रुवीय" एलएल रोगियों में बीमारी की अंतिम पुनरावृत्ति होती है। यह सक्रिय केस-खोज के बावजूद बीमारी को फैलाता रहता है। हम सभी एलएल रोगियों को एमडीटी के बाद मासिक कीमोप्रोफाइलैक्सिस प्रदान कर सकते हैं। इससे बीमारी की पुनरावृत्ति को रोका जा सकेगा। एमडीटी की सामान्य अवधि के बाद एलएल रोगियों की रक्षा करके शांडोंग ने लगभग शून्य संचरण हासिल किया।
एमडीटी के बाद एलएल रोगियों के लिए केमोप्रोफिलैक्सिस इसकी उच्च प्रभावशीलता की तुलना में बहुत सस्ती है। यदि हम लगभग 6 वर्षों के लिए देरी करते हैं, तो 2030 तक वैश्विक स्तर पर लगभग 10 करोड़ अनावश्यक नए रोगियों होने की संभावना है, जिसमें भारत में लगभग 6 करोड़ भी शामिल हैं।
नए शोध से एमडीटी के बावजूद मल्टी-ड्रग प्रतिरोधी बेसिली की उच्च आवृत्ति का पता चला है। एलएल रोगियों के लिए पोस्ट-एमडीटी कीमोप्रोफिलैक्सिस का उपयोग करना अब बहुत जरूरी है। उदाहरण के लिए, मासिक रिफैम्पिसिन + मोक्सीफ्लोक्सासिन + मिनोसाइक्लिन 100% प्रभावी होने की संभावना है।
A recorrência da doença ocorre eventualmente em até 75% dos pacientes LL "polares", mesmo depois de dar 24 meses de MDT. Isso continua espalhando a doença. Podemos fornecer quimioprofilaxia mensal após a MDT a todos os pacientes com LL. Isso evitará a recorrência da doença. Shandong alcançou a transmissão quase zero protegendo os pacientes com LL após a duração usual da PQT.
A quimioprofilaxia mensal para pacientes com LL após a PQT é muito barata em comparação com sua alta eficácia. Se demorarmos por cerca de 6 anos, é provável que haja cerca de 1 milhão de novos casos evitável em todo o mundo até 2030.
Um novo estudo de base populacional no Brasil revelou a alta freqüência de bacilos resistentes a múltiplas drogas, apesar da MDT. Agora é muito urgente a utilização de quimioprofilaxia pós-PQT para pacientes com LL.
La récurrence de la maladie survient finalement chez 75% des patients LL «polaires» même après 24 mois de PCT. Cela continue à propager la maladie malgré le dépistage actif. Nous pouvons administrer une chimioprophylaxie mensuelle après la PCT à tous les patients LL. Cela empêchera la récurrence de la maladie. Shandong a atteint une transmission proche de zéro en protégeant les patients LL après la durée habituelle de la PCT.
La chimioprophylaxie chez les patients LL après PCT est très peu coûteuse par rapport à sa grande efficacité. Si nous retardons d'environ 6 ans, il y aura probablement environ 1 million de nouveaux cas évitables dans le monde jusqu'en 2030.
Une nouvelle étude a révélé la fréquence élevée de bacilles multirésistants malgré la PCT. Il est maintenant très urgent d'utiliser la chimioprophylaxie post-PCT pour les patients LL. Par exemple, les traitements mensuels rifampicine + moxifloxacine + minocycline auront probablement une efficacité de 100%.
La recurrencia de la enfermedad ocurre finalmente en hasta el 75% de los pacientes con LL "polares" incluso después de 24 meses de MDT. Esto sigue propagando la enfermedad a pesar de la búsqueda activa de casos. Podemos administrar una quimioprofilaxis mensual después de la MDT a todos los pacientes con LL. Esto evitará la recurrencia de la enfermedad. Shandong logró una transmisión cercana a cero al proteger a los pacientes con LL después de la duración habitual de la MDT.
La quimioprofilaxis para pacientes con LL después de la MDT es muy barata en comparación con su alta efectividad. Si demoramos alrededor de 6 años, es probable que haya alrededor de 1 millón de nuevos casos evitables en todo el mundo antes de 2030.
Un nuevo estudio ha revelado la alta frecuencia de bacilos resistentes a múltiples fármacos a pesar del MDT. Ahora es muy urgente utilizar la quimioprofilaxis post-MDT para pacientes con LL. Por ejemplo, es probable que la rifampicina + moxifloxacina + minociclina administrada mensualmente sea 100% efectiva.
References
1a. 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.
2a. 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.
3a. Aggarwal A, Pandey A. Inverse sampling to study disease burden of leprosy. Indian J Med Res 132, October 2010, 438-441.
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
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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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