Global control of leprosy, an ancient infectious disease caused by Mycobacterium leprae (M. leprae), has stalled and needs new interventions. Post exposure prophylaxis (PEP) is one of the key interventions suggested to overcome the stalemate. Currently single dose Rifampicin (SDR) is the regimen of choice but new strategies and tools are required to target individuals at risk of developing leprosy or transmitting the bacterium.
We completed the PEOPLE cluster randomized trial to evaluate the impact of three different approaches to SDR PEP on new leprosy case detection rates in highly endemic villages on the Comoros and Madagascar, assessing the effectiveness of inclusion of different sets of contacts on decreasing leprosy incidence at the village level. Highly endemic villages were randomized to one of four study arms, comparing the current baseline, i.e. no PEP (arm 1), to intervention arms in which SDR PEP is provided to household contacts only (arm 2), to all contacts within a radius of 100 meters (arm 3), or to household contacts plus individuals seropositive for anti-M. leprae PGL-I antibodies living within a radius of 100 meters (arm 4). Rather than the standard dose for Rifampicin of 10 mg/kg, we offered 20 mg/kg (single double dose of rifampicin (SDDR)) in all three intervention arms. Ethical approvals were obtained at all study sites and in Antwerp.
In the Comoros’ islands of Anjouan and Mohéli, we selected highly endemic villages based on data for the period 2013-2017. In Madagascar, the first survey round served to document baseline prevalence in endemic villages, based on which the most endemic villages were randomized to the four different arms from year 2 onwards. The first survey served as a baseline and was also used to outline high risk zones within the villages allocated to study arms 3 and 4 by applying a 100m radius buffer around each household with an incident case in the preceding five years. PEP was then provided in arms 2-4. Surveys were repeated once yearly. After the first survey, risk zones were redrawn based on cases reported over the preceding five-year period and PEP was provided accordingly. Participants who did not receive rifampicin in the preceding two years could become eligible again for another dose of SDDR. The fourth and final survey was used to calculate cumulative incidence rates per study arm since baseline, with no more PEP offered.
In the Comoros the first study participant was enrolled on 11 January, 2019, in Madagascar during 2019 the baseline survey was completed. Enrolment in the trial in Madagascar started on 20 February, 2020. Over the duration of the study a total population of 110,666 have been registered in the study villages, 64,298 on Anjouan, 25,310 on Mohéli and 21,158 in Madagascar. Out of those 96,000 (86.7%) had at least one follow-up examination. In all three sites PEP was distributed as planned to 19,978 participants in total. Out of those 18,483 (92.5%) had at least one follow-up. The Covid-19 pandemic has caused some interruptions, in particular on Mohéli and in Madagascar. Despite these interruptions all four survey rounds planned have been completed with minimal delay.
In addition, we conducted an anthropological qualitative sub-study to (1) explore the (social) factors that can improve the effectiveness of the trial implementation in the 3 islands and (2) to gain a better understanding of social networks in relation to leprosy through a qualitative proof of concept study in one endemic village in Madagascar. Regarding (1), the intervention generally seemed acceptable, despite some challenges, including the perceived non-necessity of participating when not feeling ill/at risk (leprosy being linked to amputations and advanced lesions, not merely a skin patch), fears related to samples being taken (of patients and fingerpricks in arm 4 villages) with specific sensitivities related to the value of blood in the studied settings in Madagascar. Expectations about getting personal sampling results fed back remain for some participants despite the explanation during informed consent that this is not intended in trial procedures. Recommendations were shared in 2019 regarding communication aspects, confidentiality/privacy, trial procedures and acceptability (including reasons for refusals/avoidance). The COVID-19 pandemic hampered fieldwork and didn’t allow for a continuous follow-up of the implementation. Data about the social network analysis provide valuable information for the current social network study in the Comoros, including practical aspects to consider when exploring social network structures both for qualitative interviews and for surveys. Preliminary results also illustrate how clustering in space can be linked to factors other than transmission amongst individuals within a spatial cluster, such as migration from other endemic areas, and the importance of contextualizing epidemiological and molecular data on leprosy. One major finding that emerged from patients’ both present and past social networks was the possibility of transmission outside the current village of residence. Given the incubation period of leprosy, most patients noticed their first symptoms years before arriving in their current residence (where they were registered in the PEOPLE trial). This relates to a second major result, namely the common history of migration of many patients (and community members). This highlights how residence is not fixed in space and time and, in this case, mobility inside and outside the village would be important to be take into account in the analysis of transmission pathways/dynamics.
In order to correlate patterns of clustering of leprosy at village and island level with the results observed in the four study arms, a molecular study based on genotyping of M. leprae bacteria was performed. We successfully validated a new assay, called Deeplex Myc-Lep, based on multi-target deep sequencing, and conducted the first drug resistance surveillance in the Comoros. To date, we have identified no drug resistance associated mutations to rifampicin, fluoroquinolones, nor dapsone.
The pre-final results of the study were presented at the Leprosy Research Initiative meeting in Breukelen (NL) in April 2023, as well as at a regional leprosy program managers meeting on SEARO in Kolkata (India). The main conclusion of the intervention trial is that PEP does protect, at individual level as well as at community level. We also observed a strong effect of geographical distance to index cases. The biggest impact on leprosy transmission can probably be achieved through systematic screening of household contacts and close neighbourhood contacts (e.g. within 50 meters) and offering PEP in addition. There remains a clear need for exploring more potent PEP regimes.
The outcomes of this project thus have important programmatic implications for leprosy control and how to turn off the tap of ongoing M. leprae transmission.