Hansen’s disease relapse after fixed-dose multibacillary multidrug therapy
by Ximena Illarramendi.
Three decades after the implementation of fixed-dose multibacillary (MB) multidrug therapy (MDT) for Hansen’s disease , the World Health Organization (WHO) states that use of this treatment has been successful; neither disease relapse nor drug resistance are significant problems and the regimens are well tolerated by patients. However, it is important to demonstrate that fixed-dose multibacillary MDT (MB-MDT) remains effective in treating people with Hansen’s disease who have many patches or nodules (lumps) on the skin.
Relapses are an indicator of MDT effectiveness. According to the Informative Note Nº 51, 2015 from the Ministry of Health of Brazil (1), relapse cases of HD are considered to be "all cases of Hansen’s disease, regularly treated with standardized and correctly indicated official schemes, who were discharged for cure, (...) and who present new clinical signs and symptoms of active (infectious) disease. Cases of relapse in Hansen’s disease usually occur in a period of more than five years after cure."
In a study published recently in the journal 'PloS Neglected Tropical Diseases' (2), we reported that recurrence of signs and symptoms of Hansen’s disease after completion of the WHO 12-dose regimen for MB forms of Hansen’s disease is rare. We confirmed that the disease is curable and we provided further evidence of the efficacy of fixed-dose MB-MDT. We studied 713 people affected by Hansen’s disease treated over a period of 20 years within the Ambulatório Souza Araújo (ASA) outpatient service, Oswaldo Cruz Institute-Fiocruz, Rio de Janeiro, showing that return of the disease after completion of 12-dose MB-MDT is extremely rare, affecting only 1 in every 1,000 people treated per year (2).
In recent years, WHO has reported an increase in the number of relapse cases, which increased worldwide from 2,844 in 2016 to 3,893 in 2019 (3). These data do not distinguish the treatment regimen used; they include MB regimen patients (who present many lesions and a large number of bacteria in the organism), paucibacillary (PB) regimen patients (who present few lesions and low number of bacteria in the organism), and even patient who receive monotherapy (a single drug). In our study, we addressed cases of relapse only in people affected by HD who had a positive slit skin smear, regardless of the number of skin lesions and, and who received 12-dose MB-MDT.
At ASA, a reference centre specialising in Hansen’s disease, we perform slit skin smears at the moment of diagnosis and at the end of MDT treatment. Bacilloscopy allows us to observe the presence of the bacteria in the skin smear collected from four sites, the earlobes, the skin lesion and the elbow. The bacillary index (BI) helps in deciding about the best treatment regimen, because there are patients with few lesions (5 or fewer) who may be sputum smear positive and thus be indicated for treatment with MB-MDT. In the primary care setting without BI results, such patients would receive a PB regimen.
Therefore, the increase in relapse rates in endemic countries may be due to failures in older treatment regimens, as well as errors in diagnosis, with patients with many lesions and positive BI receiving PB-MDT. On the other hand, the relationship between the increasing number of relapses and the increasing volume of patients discharged for cure must be considered, in other words, the proportion not the number of relapses is key.
In this context, it is worth mentioning the definition of recurrence that we used in our study. We used the set of information obtained from the patient to make the diagnosis, that is, data from the epidemiological investigation, anamnesis, physical examination and complementary laboratory tests. Therefore, we defined a relapse case as a discharged patient who received 12-dose MB-MDT, with the standard drugs (rifampicin, dapsone and clofazimine) or alternative drugs (replacement of rifampicin and/or dapsone by ofloxacin, minocycline or clarithromycin), and who had appearance of new Hansen’s disease lesions and/or evidence of increased bacillary load.
The return of lesions may occur due to reactivation of the bacterial focus after treatment. However, the possibility of reinfection should be considered, in settings where disease control has not yet been achieved. Thus, areas with active transmission persist where already-treated persons with Hansen’s disease remain susceptible to reinfection and may re-develop the disease. The long incubation period of the disease, due to the slow multiplication of the bacteria in the body, explains relapses several years after discharge from MDT, as observed in our study, when cases were recorded up to 15 years post-MDT.
In conclusion, for the ‘zero leprosy’ roadmap, the treatment of persons affected by Hansen’s disease and the use of 12-dose MB-MDT for those with six or more skin lesions or who have detectable bacillary load should be continued. This is one of the four pillars of the WHO Global Hansen’s disease Strategy 2021-2030 ‘Towards Zero Leprosy (4).
IH Editorial Board :
Patrícia D. Deps and Simon M. Collin.
Victória Pagani de Souza and Giulia Cuppertino de Castro.
Daniel Mariani Favalessa and Simon M. Collin.
MINISTÉRIO DA SAÚDE. NOTA INFORMATIVA Nº 51, DE 2015 CGHDE/DEVIT/SVS/MS. Acessado em 8/9/2021. Disponível em: https://www.saude.pr.gov.br/sites/default/arquivos_restritos/files/documento/2020-04/notainformativa51recidivaresisteinsuficienciamedicamentosanahanseniase.pdf
Nery JAC, Sales AM, Hacker MAVB, Moraes MO, Maia RC, Sarno EN, et al. (2021) Low rate of relapse after twelve-dose multidrug therapy for hansen’s disease: A 20-year cohort study in a brazilian reference center. PLoS Negl Trop Dis 15(5): e0009382. https://doi.org/10.1371/journal.pntd.0009382
World Health Organization. Global leprosy (Hansen disease) update, 2019. Wkly Epidemiol Rec 2020;95, 417–440. Available from: https://www.who.int/wer/2020/wer9536/en/.
Estratégia Global de Hanseníase 2021–2030 – “Rumo à zero hanseníase”. Acessado em 9 de setembro de 2021. Disponível em: https://www.who.int/pt/publications/i/item/9789290228509