Leprosy Mailing List – July 12, 2018
Ref.: (LML) Manifest against the implementation of U-MDT
From: Claudio Salgado, Marituba, Pará, Brazil and Colleagues from Brazil and USA
Dear LML colleagues,
We also believe the discussion about adopting U-MDT treatment regimens for leprosy clearly needs debate from all stakeholders, but it is really important for the welfare of our patients that we always keep the main focus on new and better treatment options for them. In general, leprosy patients are poor, and have no access to other possible drugs, so they rely on public health systems, most of the time with no other options. In our view, MDT is a classical case of the real-life situation here, patients can only take the medication available to them. Thus, it is really important to understand that although we are aware of the millions of people treated and cured by MDT over the years, the greater need is for new, better and less toxic drugs, not shorter regimens with the same old drugs that have known side effects or toxicities.
Considering the important topics raised by Drs. Lockwood and Walker (LML, July 6, 2018), we would like to make comments that we believe are crucial for the future of leprosy treatment and, of course, leprosy research. Therefore, we will make comments point by point.
We sincerely do not understand the idea that "moving to a newer shorter regimen means that toxicities need to be better monitored" and that "it also offers opportunities for strengthening better case management of leprosy patients and their complications". We have been treating leprosy patients with MDT for decades. We have treated millions of MB patients for 1 to 2 years or even more, and people – patients and doctors – have been dealing with that for a long time. What is the point of better monitoring toxicities with a possible shortening of MDT? More to the point, how can U-MDT implementation bring opportunities for better case management and fewer complications? It is really difficult for us to understand how U-MDT use will show improvement in these areas based on the facts as we know them.
Concerning the absence of evidence that the PB regimen is failing, it is hard to say. There are only a few good studies of cohorts of PB patients followed over the years. Besides having a few PB patients relapsing as PB again, there are many patients classified and treated as PB, that we later had to reclassify to MB when they appear years later with disease activity likely due to misdiagnosis. Since they were released by cure, administratively, after 6 doses, when they enter in the system again, they are not classified as relapses, they are classified as a diagnostic error, even by doctors that have never seen the patient before. This is one of the sources of our beliefs about PB/MB misclassifications. Are we correct? But we do not believe this should be a primary concern about this U-MDT discussion. The main problem is with the MB patients, especially those who are AFB positive on slit skin smear.
It is true that clinical improvement of skin lesions, fall in the BI, and relapse rate were the only three components to evaluate the response of leprosy patients to antibiotics 30 or 40 years ago, but this should not be the case anymore. We cannot accept this in 2018. In the last 3 or 4 decades there have been huge advances in understanding the immunology and use of treatment strategies to achieve better outcomes for patients, and new data have been produced about leprosy patients with different techniques. Electroneuromyography and ultrasound, serology using different markers, and molecular biology to detect M. leprae DNA by real time PCR are among the techniques that are becoming more routinely used, including the old but not outdated Shepard technique that can tell us if a given strain has drug resistance to any drug in the standard MDT regimen. Why not use all those tools with our leprosy patients? Science and medicine must be used to improve the outcomes for our patients and to improve our knowledge concerning their management. Nerve evaluation, forgotten in many trials, including those of U-MDT, cannot be outside of the boundaries used to evaluate leprosy patients.
Concerning the decrease in the BI over time in the Penna work, as cited by Lockwood and Walker, this is true. However, we must remember a few things about this odd bacterium: 1. M. leprae has a very slow rate of multiplication, 12-14 days, the longest of any bacterium; 2. Studies with a single dose of rifampicin chemoprophylaxis showed that it could delay the diagnosis of leprosy by two years in the treated group. Therefore, just showing that there is a decrease in the BI after 6 U-MDT doses within 4.7 years of follow up is not a long enough time to say that the patients are cured of disease. Based on the very slow growth of M. leprae this assumption is false, one would need a much greater time of follow-up. If it is true that one capsule of rifampicin given to a contact who is not AFB positive may delay the diagnosis of leprosy for two years, widespread undertreatment of an entire class of leprosy patients with U-MDT could result in serious problems many years later. These problems will likely only appear in 5, 10, or >15 years from now. Brazilian patients and leprosy patients from any other country do not deserve to be treated in such a haphazard or irresponsible manner.
The other trials comparing shorter treatment regimens have similar deficiencies. They did not evaluate the number or percentage of patients that were really cured and did not evaluate nerve damage. Bangladesh is a case apart. A seven-year trial that doesn't have one relapse raises real doubts, particularly since they used the same MDT regimen. We have experienced relapses in patients even after completing 24 doses of MDT. We have many more relapses with 12 doses. And even in Penna's study, there were 7 times the number of relapses with the six doses of U-MDT than the standard MDT regimen, and some of these occurred in under 5 years, reflecting the likelihood of undertreatment, a real cause for concern that seems to have been overlooked.
When Lockwood and Walker say that "If a shorter regimen is to be introduced then more attention needs to be given to the diagnosis of leprosy", once again we do not understand. We have been saying that there is already a lack of proper diagnosis in leprosy now. Absence of diagnosis is to be partially blamed for the low number of cases of leprosy that we see today in the world. Patients who were released from the leprosariums into the surrounding community mostly remained there, establishing towns around the former colonies populated by their descendants, having much higher rates of leprosy than other nearby towns. For people who are not aware of the disease, leprosy is over, nobody really thinks that it still exists anymore. In addition, expertise is lost, there are fewer dedicated leprosy dermatologists remaining. So, there is no connection at all between a short U-MDT implementation and diagnosis. These are different things altogether.
"Counting lesions will no longer be needed, but health workers will need better training in recognizing leprosy"? Health workers certainly need to be trained now, and in order to be well trained, it should be by experienced leprologists, while they still exist. We do not need a shortened regimen of old drugs to do this. Training must be included in the front line of the fight against leprosy, now. Patients need more attention now, with or without a shortened treatment and yes, we need to detect nerve damage, as said above. It is true.
After so many years of research, why do we still know so little about leprosy reactions? There is still discussion about why some people have reactions while others do not. Reactions could be a result of bacilli multiplication? If not, we need to better understand the disease interfaces on pathology and immunology. If yes, then we have a problem, a big one. How about different strains giving different results? Do we know that? Do we know if our patients have only one strain or two or more strains, with possible drug resistance? Do we know if a strain has a higher capacity of developing reactions or if a strain is more resistant to antibiotics? We do not know. These are all basic questions for any disease that we want to control.
Unfortunately, we still need to work hard to show the world that leprosy is a big problem, particularly in Brazil, and that leprosy patients need better management and new drugs that are more effective and less toxic, some of which are already available. We need to show that patients are often forgotten by inflexible or uncaring systems, and that they are living with sequelae, lost among other poor people with equal or worse health problems struggling in our communities. A shorter, less effective, regimen of MDT definitely will not bring this to our patients. Not at all.
Thanks for the opportunity of sharing our thoughts with this unique community.
Claudio Salgado, presidente Brazilian Leprosy Society (SBH), Professor at Pará Federal University
Marco Andrey Frade, vice-president SBH, Professor at University of São Paulo
Isabela Goulart, scientific diretor SBH, Professor at Uberlândia Federal University
Laila de Laguiche, South Brazil representative and international public relations SBH
John Spencer, Professor at Colorado State University
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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