The implementation of multidrug therapy (MDT) for leprosy control has been important for the reduction of the overall burden of disease in the world. However, the emergence of new cases every year in endemic countries is of great concern. In 2015, out of the 210,758 new cases in the world, India occupied first place with 60.1% of the cases, and Brazil is ranked second with 12.5% [
4]. The incidence in children suggests active transmission of the disease in approximately 100 countries [
28]. In the westernmost state of Amazonia, the situation is similar. Acre occupies the third place in the number of new cases in Brazil and contributed to the occurrence of 125 new cases; in 2017, 10 of these cases were in children/teens under 15 years of age [
3]. This situation points to the need for new global and local preventive measures that facilitate the control of the disease in scenarios of hotspot
M. leprae transmission. Cases of leprosy recurrence in patients that were considered cured appear in the surveillance system and can be erroneously related to factors other than new infections. Among the strategies for controlling and monitoring the success achieved by leprosy control programs is the identification of the underlying mechanisms involved in the recurrence of the disease in the target population.
Conceptual model: rationale and proposition
One of the novelties of the present study is the interpretation of the results while considering the challenging agenda for the elimination of leprosy in Brazil. In this context, we considered heterogeneous underlying mechanisms involved in leprosy recurrence. In order to identify these mechanisms with the available data, we assumed that each one had a characteristic length of time from release from treatment to leprosy recurrence. In our proposed evaluation, we consider the time interval under 5 years as having the underlying mechanism of insufficient therapy based on the operational classification error at the time of the first diagnosis. In such a case, multibacillary leprosy cases classified as paucibacillary receive treatment with insufficient doses, which might increase the likelihood of recurrence [
31]. When the time interval is ≥5 < 15 years, the underlying mechanism is very likely bacillary persistence, which refers to the adaptive capacity of
M. leprae bacilli to remain inactive under conditions of low metabolism during treatment and reacquire its active metabolic form sometime after release from treatment, causing new signs of disease activity [
32]. When the time interval is ≥15 years, the underlying mechanism favours new infection. Although this mechanism is hard to scientifically demonstrate, we considered it in our study using logical deduction. Leprosy recurrence cases that present with long time intervals between the first and second treatments are mainly found in those patients that remain continuously exposed to high bacillary contact in local transmission hotspots [
33‐
35].
Underlying mechanisms in leprosy recurrence
In our study, we tested the dose-response effect of MDT. Accordingly, we expected that the lowest dosage (i.e., MDT
0–9) would imply a greater probability of recurrence in a shorter period (under 5 years). This relationship was observed mainly in patients submitted to the following schemes: MDT
0–9 and MDT
10–19. Conversely, higher dosage (i.e., MDT
30+) can lower the likelihood of recurrence. This was associated with a longer time interval between release from treatment and recurrence, as shown for MDT
20–29 and MDT
30+. In agreement with the literature and our conceptual model, we interpreted these results as a consequence of the mechanism of therapeutic insufficiency for the patients erroneously classified as paucibacillary leprosy, such as those in the group of MDT
0–9, which consequently led to inadequate treatment and disease recurrence [
36‐
38].
Accordingly, patients submitted to ROM and DDS schemes presented a bimodal distribution for the relevant time intervals. Their first peaks were equivalent and corresponded to a high probability of therapeutic insufficiency. The MDT0–9 scheme also presented a greater predominance in the time interval under 5 years, which is related to therapeutic insufficiency according to the Brazilian Ministry of Health.
A higher incidence rate of leprosy recurrence was observed for the cases submitted to ROM, MDT0–9 and MDT10–19, compared to MDT30+. However, there is no statistical difference between incidence rates of leprosy recurrence of the DDS and MDT30+ schemes. We emphasize that this similarity between these diametrically opposed therapeutic schemes had contributions from mechanisms other than the insufficient therapy mechanism. Particularly, the MDT30+ scheme showed a protective effect compared to the ROM, MDT0–9 and MDT10–19 schemes for leprosy recurrence.
In addition to the insufficient therapy mechanism, we observed the likelihood of the mechanism of bacillary persistence. For instance, there is a representative number of cases (11%, 23/224) that showed leprosy recurrence associated with a time interval of 10.5 and 12.5 years. Balagon et al. found in their study a peak of leprosy recurrence between 11 and 12 years, suggesting that this peak is related to the activation of dormant organisms that did not undergo effective MDT [
39,
40]. Additionally, for recurrent cases that occurred between 10 and 15 years—especially those who had more than one recurrence episode—we emphasize the importance of investigating bacterial resistance through molecular analysis. For instance, we have currently been testing contacts of new leprosy cases for the possibility of infection by resistant bacteria. So far, this mechanism does not seem to be widespread in Acre (data not shown/not published).
One important finding of our study is that patients given more prolonged treatments (e.g., MDT
20–29 and MDT
30+) have a lower risk of leprosy recurrence. This obviously challenges recent studies demonstrating the ubiquitous efficacy of the newly proposed therapeutic scheme known as the uniform multidrug therapy (MDT-U). MDT-U is a shorter dosage scheme for the treatment of MB leprosy and contains the addition of one drug to PB leprosy [
41]. Of course, this is a matter of intense debate, and it is not within the scope of the current study.
Another important finding is that the mechanism of new infection in leprosy recurrence is both epidemiologically important and neglected. For instance, the second peak of the time interval in patients that had DDS for a therapeutic scheme is emblematic. Almost 50% (22/45) of the patients in the DDS therapeutic scheme showed leprosy recurrence in 15 or more years after the cure. This is in congruence with the high and positive linear effect of the incidence of new cases—especially in children under 15—on incidence of recurrent leprosy cases in the municipalities of Acre. The mechanism of new infection is therefore one of the causes of leprosy recurrence [
42‐
46].