Potential 'Game Changer' for Leprosy Prevention

A single dose of rifapentine reduced the incidence of leprosy among household contacts of patients with the infectious disease, a cluster-randomized trial out of China found.

In an intention-to-treat analysis, the cumulative incidence of leprosy among 7,450 household contacts was 0.09% with an oral dose of rifapentine over 4 years of follow-up, as compared with 0.33% with a single dose of rifampin, and 0.55% with no intervention at all.

That difference for the rifapentine group versus controls translated to an 84% lower risk (cumulative incidence ratio 0.16, multiplicity-adjusted 95% CI 0.03-0.87, P=0.02), reported Hongsheng Wang, MD, PhD, of the National Center for Leprosy Control at the Chinese Center for Disease Control and Prevention in Beijing, and colleagues in the New England Journal of Medicine.

No significant difference in cumulative incidence was seen between the rifampin and control groups, though a per-protocol analysis suggested an effect, and the researchers said both antimycobacterial agents are being considered in China's leprosy eradication program.

Leprosy is caused by Mycobacterium leprae, and untreated patients with multibacillary-type leprosy are generally thought to be the main source of transmission, according to the researchers. One study estimated that the risk of transmission for household contacts is 1,300 times greater than the general population.

Prophylactic treatment of contacts can wipe out infections before the development of symptoms, which commonly include skin lesions and peripheral nerve involvement that can occur within a year, but sometimes decades after infection, according to the World Health Organization (WHO).

Also known as Hansen's disease, the chronic infectious disease has stubbornly persisted despite the curable multidrug treatment of dapsone, rifampin, and clofazimine, with roughly 200,000 new cases worldwide annually in recent years.

Single-agent rifampin -- the most bactericidal agent in the multidrug regimen -- has been recommended since 2018 by the WHO for prevention in household contacts, but the endorsement was met with some concern over privacy issues and the fear of drug resistance, given rifampin's critical use in treating tuberculosis.

Rifapentine, meanwhile, is an FDA approved drug for treating tuberculosis as well. The antimycobacterial has a longer half-life than rifampin and in mouse models also showed greater bactericidal activity against M. leprae, the study authors noted.

David Scollard, MD, PhD, formerly the director of the National Hansen's Disease Programs in Baton Rouge, Louisiana, called rifapentine's ability to provide protection for close contacts "a potential game changer" for leprosy control.

In an accompanying editorial, he noted that the WHO made its recommendation for postexposure prophylaxis with rifampin based on results of a randomized trial from Bangladesh. That study showed a 57% reduction in leprosy incidence over 2 years, yet household contacts -- the group at highest risk -- experienced the least benefit, and after 2 years there was no difference in new leprosy cases between the rifampin and placebo groups.

With rifapentine, he said, the duration of effect doubled that of rifampin in the Bangladesh trial, and the current study was performed in a region with low endemic levels of M. leprae, where an effective prophylactic regimen is "desirable globally."

Scollard, who is now retired, also raised the question of how widely to implement a more effective prophylactic regimen. (China's confidentiality requirements to avoid discrimination for leprosy patients meant the trial did not include neighbors and social contacts of index patients.)

"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," he noted. "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."

Plus, Scollard said, widespread administration could theoretically build drug resistance and result in unnecessary treatment. In the rifampin prophylaxis trial, for example, the overall number of contacts needed to treat was 297 to prevent a single case of leprosy.

Wang and colleagues' open-label cluster-randomized trial was conducted in four provinces in Southwest China and included 207 clusters -- counties or districts with at least two household contacts of index cases -- assigned to one of three groups:

• Rifapentine: 68 clusters with 809 index patients and 2,331 household contacts
• Rifampin: 71 clusters with 969 patients and 2,760 contacts
• Control: 68 clusters with 827 patients and 2,359 contacts

Dosages of rifapentine and rifampin were 600 mg for individuals 15 years and older, or 450 mg for kids ages 10 to 14 years.

Contacts had an average age of 33 years, and most were first-degree relatives of a patient with leprosy. For the index patients, the vast majority had new cases (98%) of multibacillary-type leprosy (82-90%).

The primary endpoint was the cumulative incidence of leprosy among the household contacts at 4 years in the intention-to-treat population, with a contact defined as anyone living in the same house as an index patient for a total of at least 6 months -- anytime from 6 years prior to diagnosis or 1 month after starting multidrug therapy.

Over the 4-year study period, 24 cases of leprosy were reported among contacts, two in the rifapentine group, nine in the rifampin group, and 13 among the controls who underwent no intervention.

Secondary outcomes included the cumulative leprosy incidence among household contacts at 2 years, where no significant differences were seen between groups.

No severe adverse events were observed in any of the groups.

Researchers said their findings had limitations, including that they may not be generalizable to areas with high endemic levels of leprosy.

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