A New Step in Postexposure Prophylaxis for Leprosy
David M. Scollard
N Engl J Med 2023; 388:1904-1905
DOI: 10.1056/NEJMe2302667
Infection with Mycobacterium leprae is curable with a combination of dapsone, rifampin, and clofazimine (multidrug therapy), as recommended by the World Health Organization (WHO) in 1982. The use of this multidrug regimen led to an initial rapid decline in the global prevalence of M. leprae infection, a reduction that was bolstered by the removal of many previously cured patients from national registries. Encouraged, the WHO coordinated a global effort from 1990 to 2000 to eliminate leprosy as a public health problem through the use of multidrug therapy on the premise that curing new cases would interrupt transmission. Initially, this program looked promising; however, after 2000, the decline in leprosy cases stalled, and the number of new cases and prevalence have stubbornly remained at a steady plateau.1 Leprosy control programs struggled, and surveillance floundered.2 Leaders and participants at national and international leprosy meetings worried openly about how to further reduce the number of new cases.
Rifampin is the most highly bactericidal component of multidrug therapy for leprosy. Could it provide effective postexposure prophylaxis? A randomized, controlled trial, in which contacts of patients with leprosy were assigned to receive single-dose rifampin as postexposure prophylaxis or placebo, showed an overall protective effect of 57% with single-dose rifampin in the first 2 years after administration.3However, this trial also revealed two serious drawbacks of postexposure prophylaxis with rifampin. The least benefit was observed among the participants at the highest risk, household contacts; neighbors and social contacts received the main benefits of rifampin. In addition, after 2 years, the percentage of new cases in the rifampin group was the same as that in the placebo group. Despite these and other concerns,4 the overall results were promising enough to prompt the WHO in 2018 to recommend single-dose rifampin as postexposure prophylaxis worldwide.
Now there are new possibilities for the prevention of leprosy among close contacts. In this issue of the Journal, Wang and colleagues5 report the results of a large, randomized, controlled trial in which household contacts of patients with leprosy were assigned to receive a single 600-mg dose of rifapentine or rifampin or no prophylaxis (control). Among the household contacts, the single 600-mg dose of rifapentine provided significant protection as compared with the control group. Fewer cases were also observed in the rifapentine group than in the rifampin group, although the difference was not significant.
Providing protection in close contacts is a potential game changer in leprosy prevention, and this trial is important for two additional reasons. The benefit of rifapentine was observed through all 4 years of follow-up, which is double the duration of the effect observed with rifampin. In addition, this trial was conducted in a region where the endemic level of M. leprae infection is low, rather than in an area with a high endemic level as in previous trials of postexposure prophylaxis with rifampin. Postexposure prophylaxis that is effective in regions with low endemic levels of infection is desirable globally.
Exactly 150 years ago, Armauer Hansen discovered the leprosy bacillus, years before Robert Koch identified the tubercle bacillus. However, treatment regimens for tuberculosis have led the way for leprosy treatment, largely because M. tuberculosis is cultivable but M. leprae is not. Prophylaxis regimens for M. leprae infection are following the same path.
Rifapentine has become a familiar component of antituberculosis treatment and prophylaxis regimens,6 but it has not been used to treat leprosy. Experimental studies using the mouse footpad model to grow M. leprae showed that rifapentine was highly bactericidal.7 Subsequently, a molecular viability assay has confirmed and extended this finding; in direct comparisons, rifapentine kills M. lepraesignificantly more effectively than rifampin.8
If a more effective prophylactic regimen is devised, who should receive it beyond household contacts? Identifying social contacts and offering rifapentine for postexposure prophylaxis could determine empirically whether this agent provides a longer duration of protection than rifampin among social contacts. However, a selective approach to postexposure prophylaxis is desirable because alerting social contacts and neighbors about a nearby case of leprosy arouses concerns about confidentiality, stigma, and discrimination. Widespread administration might result in treating many people unnecessarily and might also risk building resistance.
A sensitive and specific screening test that could be used in broad community or school-based health activities could enable a selective application of postexposure prophylaxis. The incubation time for leprosy may be several years, but no test yet exists to enable the identification of latent or subclinical infection with M. leprae, although recent multibiomarker tests show promise.9 Without such tests and further study, “latent” and “subclinical” remain theoretical concepts with respect to M. leprae infection.
Genes associated with susceptibility or resistance to M. leprae have been identified.10 Genetically susceptible persons could theoretically be identified and given postexposure prophylaxis. Currently, however, no genetic screening test for leprosy susceptibility is available.
The observations by Wang and colleagues indicate that successful postexposure prophylaxis in household contacts is possible. Rifapentine should now be considered in planning future trials of postexposure prophylaxis for leprosy and possibly also in any potential new version of multidrug therapy. Recent experience with rifampin as postexposure prophylaxis has yielded many lessons about logistics and implementation that could smooth the way for the use of other prophylactic agents. Much remains to be done, but these new findings with rifapentine provide additional energy in the implementation of postexposure prophylaxis for leprosy.
