Low rate of relapse after twelve-dose multidrug therapy for hansen's disease: A 20-year cohort study in a brazilian reference center

Abstract

The World Health Organization has raised concerns about the increasing number of Hansen disease (HD) relapses worldwide, especially in Brazil, India, and Indonesia that report the highest number of recurrent cases. Relapses are an indicator of MDT effectiveness and can reflect Mycobacterium leprae persistence or re-infection. Relapse is also a potential marker for the development or progression of disability. In this research, we studied a large cohort of persons affected by HD treated with full fixed-dose multibacillary (MB) multidrug therapy (MDT) followed for up to 20 years and observed that relapses are a rare event. We estimated the incidence density of relapse in a cohort of patients classified to receive MB regime (bacillary index (BI) > 0), diagnosed between September 1997 and June 2017, and treated with twelve-dose MB-MDT at a HD reference center in Rio de Janeiro, Brazil. We obtained the data from the data management system of the clinic routine service. We linked the selected cases to the dataset of relapses of the national HD data to confirm possible relapse cases diagnosed elsewhere. We diagnosed ten cases of relapse in a cohort of 713 patients followed-up for a mean of 12.1 years. This resulted in an incidence rate of 1.16 relapse cases per 1000 person-year (95% CI = 0.5915-2.076). The accumulated risk was 0.025 in 20 years. The very low risk observed in this cohort of twelve-dose-treated MB patients reinforces the success of the current MDT scheme.

Fig 1. Flow-diagram of the Fiocruz Hansen disease Reference Center Cohort.

The inclusion criteria considered patients who exhibited a BI higher than 0 at diagnosis, were treated with the 12-dose MB-MDT scheme between 1998–2018, and who were followed-up at the Souza Araujo Outpatient Clinic after release from treatment. Patients were followed-up at least annually (except for those censored because of age or death). Linkage of the clinic data with the National HD registry SINAN database was performed to retrieve any relapse cases not diagnosed at the clinic due to change of address. Then, the patients in the follow-up cohort were grouped according to the length of the 12-dose MB-MDT treatment. BI, bacillary index; MB, multibacillary; MDT, multidrug therapy.

Fig 2. Spline curve of the annual bacillary index (BI) mean values in 12-dose MB-MDT Hansen disease patients.

Progressive decrease of the BI obtained from slit-skin smear samples of non-relapse cases during the first years after release from treatment (full line). Observe that positive BI values remain long after release from treatment. Relapse cases (dotted line), however, show greater variability, possibly due to the small number, and display BI increases before relapse.

Fig 3. Kaplan-Meier Cumulative Risk of relapse in 713 patients treated with 12-dose MB-MDT.

The survival curve shows the proportion of people affected by Hansen disease without relapse according to the period of follow-up. Y-axis of the curve is the cumulative probability of relapse. The X-axis represents the survival duration. The length of the horizontal lines is the interval terminated by the occurrence of relapse events and the heights between horizontal lines illustrate the change in the cumulative probability.