Leprosy Mailing List – December 9, 2019
Ref.: (LML) We need to talk about this: rifampicin daily, not monthly
From: Francisco Almeida, Recife, Brazil
Dear Dr. Pieter,
I consider that one of the main successes in the control of any infectious disease concerns the treatment that is aimed at patients who are affected by this disease, as well as epidemiological and prophylactic strategies.
Decentralization of actions has promoted, over the years, a relative success in diagnosing new cases, but remains inefficient for several reasons that are currently beyond the scope of this message1.
I have recently been conducting extensive literature review research mainly on the aspects that concern the implementation of multidrug therapy by the World Health Organization, from the creation of WHO STUDY GROUP to the present day and I have noticed that there are many gaps to be filled and clarified in the WHO reports on this.
The main aspects concern the intermittent use of rifampicin and the motivations that led to the determination of treatment time with the option of using only 600mg of rifampicin per month2.
Comparison trials of the efficacy of rifampicin used in this way in the treatment of leprosy recommended by the World Health Organization are scarce and noteworthy, and the cost of daily use of rifampicin remains the main reason for adopting this regimen, as well as avoiding what WHO has termed the "anarchic use of rifampicin".
Another aspect is about the time of treatment, when the issue becomes even more controversial, since there was no consensus on this aspect. The concern was patients' lack of adherence to prolonged treatment, and, the consequent development of rifampicin resistance, and decisions were made considering that, 24 treatment doses would be sufficient to suppress endemic transmission and prevent this occurrence.
As the WHO itself states, "discussions progressed smoothly in the formal setting of the meeting, but many important topics were also addressed in the more informal context at participants' hotels. Indeed, it was the author's impression that consensus on at least one essential point (possibly the standard regimen for MB patients) was reached during one of these "extramural" sessions"2.
When WHO decided to further reduce this treatment time to the 12 currently recommended doses, in the seventh report in 1998, insecurity in the actual cure of patients increased significantly for leprologists who followed patients over the long term. The WHO itself defined that the samples that supported this positioning were small and incomplete, with the results obtained impossible to be compared. Even so, the proposition was taken to term3.
Whatever strategy is taken in relation to leprosy, the consequences only appear many decades later. Today, in all corners of the world, leprologists have come across cases unresponsive to treatment, searching in some countries (in vain) mechanisms of drug resistance only in the 3 Drug Resistance Determinant Region (DRDR)-loci, that include dapsone and rifampicin (ofloxacin is considered a secondary drug). Mostly the results are negative, which strengthens the idea that drug resistance in leprosy is rare and occasional. Therefore, the treatment offered to patients is supposedly effective4.
In a multicenter study (2018) conducted in 25 countries, including Brazil, published in the journal Nature Communications, the authors identified a wide range of drug resistance-associated mutations. Mutations such as those associated with ribD and fadD9 genes, as well as nonsense mutations in the nth excision repair gene associated with several different single nucleotide polymorphisms (SNPs), all of which are found by extended analysis beyond DRDR.5
There are still ongoing studies (Reja, 2018), which deal with another mechanism of drug resistance due to the amplification of the already known genomic reduction of Mycobacterium leprae (ML) that occurs during multidrug treatment through a mechanism called "TCC repeats", whose measurement of the problem. It is still totally unknown and which add one more chapter to ML.6
I have worked at a Leprosy Reference Center in Brazil for several years. My relapse rate for L-Lep patients with initial BI> 3 in 10 years who used 24 treatment doses is 100%. Patients clinically classified as Boderlines-Boderlines this relapse rate is around 95% (data not show).
These patients continue to develop leprosy reactions throughout the follow-up period after MDT suspension and only improve when they are retreated. These cases in most other services continue to be conducted for several years with prolonged corticosteroid therapy and thalidomide, whose use is permitted in Brazil. Consequently, several complications of prolonged immunosuppression arise and sequelae and disabilities only increase day by day.
Now experts report an important study that identified a protein, called antigen 85 (Ag85), which is only expressed in leprosy lesions, even in lesions of type 1 leprosy reactions, when there is bacillary multiplication. With this knowledge, the thought of type 1 leprosy reactions as a purely immunological phenomenon needs to be reviewed and expanded, especially in patients who develop leprosy reactions after discontinuation of treatment.7
Several other studies associate the occurrence of type 2 leprosy reactions with the increase of PGL-I indices, the progressive increase of BI and consequently the patients' relapse after the conclusion of 24-dose multidrug therapy.8-9-10
Importantly, in the USA patients receive 24 doses of treatment using 600 mg/day of rifampicin, associated with dapsone and usually clarithromycin, ofloxacin (adults) or minocycline, with a negligible relapse rate, due to the use of this treatment modality11. Gelber has always advocated daily rifampin use. He has opposed treatment with WHO blisters since 1984. He needs to be listened to and considered, in my point of view.12-13-14
It would be extremely inappropriate these days to continue advocating the multidrug treatment available as effective for the treatment of leprosy. Particularly in anergic and bacilliferous patients, who are mainly responsible for maintaining the leprosy transmission. We are talking about the same treatment regimen used for an infectious disease for over 40 years!
No known infections are treated with intermittent antibiotic therapy. We are far from knowing all the secrets of ML. Underestimating the abilities of this enemy of ours does not seem like a good strategy.
Despite agreeing with Dr. Joel Almeida in all his manifestations in the LML, I am worried about the propositions of using chemoprophylaxis (also intermittently) for this group of patients. This may cause in the not too distant future the development of drug resistance to secondary use drugs such as ofloxacin and other quinolones, as well as clarithromycin and minocycline, if these drugs are to be used for this purpose.
In my Leprosy Reference Center, without following the recommendations, I keep some patients on prolonged treatment. Their progressive improvement and the lower need to manage the occurrence of leprosy reactions are clear. I have also treated some patients with daily rifampicin use. The response to treatment always was excellent, with a significant increase in bacilloscopic index (BI) reduction log beyond 0.5 to 0.8 units/year. None of these patients have relapsed (so far 11 years later), although this locality is a hyperendemic area.
Instead of pursuing new regimens with other drugs, it would be much more productive to adjust to the three drugs already used by using rifampicin daily. This therapeutic scheme is already made in the USA and proves to be safe and much more effective15. In those cases of proven drug resistance to rifampicin, then yes: let's use new drugs as effective as rifampicin daily, not monthly.
It is not fair to distinguish between patients living in developed countries such as the United States and developing countries such as India and Brazil. The cost of rifampicin is no longer a plausible reason to justify the use of a treatment regimen that, day after day, seems to be inefficient for leprosy treatment.
We will not be able to control leprosy if we do not join efforts to provide better quality treatment to our patients, as well, of course, as other necessary actions, such as medical training in medical schools, contact examination and surveillance of treated patients. These patients are simply discharged for "pseudo-healing", perhaps in a failed attempt to mask the epidemiological indicators of the disease.
Sincerely,
Francisco Almeida.
MD Dermatologist and Leprologist
Professor of Dermatology (Mauricio de Nassau University Center)
Northeast Regional Representative of the Brazilian Society of Hansenology (SBH)
Recife - Pernambuco
Brazil
References:
1. NAAZ F, MOHANTY PS, BANSAL AK, KUMAR D, GUPTA UD. Challenges beyond elimination in leprosy. Int J Mycobacteriol. 2017 Jul-Sep;6(3):222-228.
2. CHANDORKAR AG, BURTE NP, GADE RK, BULAKH PM. Once monthly rifampicin (1200 mg) plus daily dapsone (100 mg) and clofazimine (100 mg) in the initial treatment of lepromatous leprosy. Indian J Lepr. 1984 Jan-Mar;56(1):63-70.
2. WHO. Multidrug Therapy against Leprosy Development and Implementation over the Past 25 Years. Geneva: World Health Organization, 2004.
3. WHO Expert Committee on Leprosy (Seventh Report). WHO Technical Report Series, no. 874. Geneva: World Health Organization, 1998.
4. BENJAK A, AVANZI C, SINGH P, LOUISEAU C et al. Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae. Nat Commun. 2018 Jan 24;9(1):352.
5. CAMBAU E, SAUNDERSON P, MATSUOKA M et al. Antimicrobial resistance in leprosy: results of the first prospective open survey conducted by a WHO surveillance network for the period 2009-2015. Clin Microbiol Infect. 2018 Dec;24(12):1305-1310.
6. REJA AHH, DE A, PATRA PK, et al. Genomic Reduction at TTC Repeats in the Bacterial Genome of Treated Cases of Hansen's Disease: A Possible Survival Mechanism of Mycobacterium leprae. Indian J Dermatol. 2018 Nov-Dec;63(6):449-454.
7. SAVE MP, DIGHE AR, NATRAJAN M, SHETTY VP. Association of viable Mycobacterium leprae with Type 1 reaction in leprosy. Lepr Rev. 2016 Mar;87(1):78-92.
8. BRITO MDE F, XIMENES RA, GALLO ME, BÜHRER-SÉKULA S. Association between leprosy reactions after treatment and bacterial load evaluated using anti PGL-I serology and bacilloscopy. Rev Soc Bras Med Trop. 2008;41 Suppl 2:67-72.
9. SOUZA, LW. Leprosy reactions in discharged patients following cure by multidrug therapy. Rev. Soc. Bras. Med. Trop. v.43, n.6, p.737-739, 2010.
10. MALHOTRA K, KULSHRESHTHA D, SHUKLA S, HUSAIN N. ENL developing 10 years after leprosy treatment masquerading as atypical-mycobacterial infection. QJM. 2015 Nov;108(11):905-6.
11. HSRA - Health Resources & Services Administration. Avaiable in https://www.hrsa.gov/hansens-disease/diagnosis/recommended-treatment.html. Accessed in 08/12/2019.
12. GELBER RH. Another View of the Therapy of Leprosy. Antimicrob Agents Chemother. 1998 Dec;42(12):3334-6.
13. GELBER RH, BALAGON VF, CELLONA RV. The relapse rate in MB leprosy patients treated with 2-years of WHO-MDT is not low. Int J Lepr Other Mycobact Dis. 2004 Dec;72(4):493-500.
14. GELBER RH, GROSSET J. The chemotherapy of leprosy: an interpretive history. Lepr Rev. 2012 Sep;83(3):221-40.
15. DACSO MM, JACOBSON RR, SCOLLARD DM et al. Evaluation of Multi-Drug Therapy for Leprosy in the United States Using Daily Rifampin. South Med J. 2011 Oct;104(10):689-94.
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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