Chemoprophylaxis in the prevention of leprosy

Abstract

National policies need to be reviewed in the light of new evidence supporting a single dose of rifampicin

In the accompanying paper, Moet and colleagues report a randomised controlled trial of chemoprophylaxis using rifampicin in household contacts of patients with newly diagnosed leprosy.¹ The potential for chemoprophylaxis to reduce transmission of leprosy caused much interest in the 1960s and 1970s. A series of trials was conducted in household contacts and in highly endemic communities using dapsone, usually given twice weekly over a period of years. A meta-analysis based on 12 of these trials (six randomised controlled trials and six non-randomised controlled trials) showed that dapsone provided significant protection (relative risk 0.4, 95% confidence interval 0.29 to 0.55) against leprosy.² Although the efficacy rate in community trials was higher than in trials in household contacts the numbers needed to treat to prevent one new case were also higher.

Interest in chemoprophylaxis waned in the 1980s and 1990s with the introduction of short course multidrug treatment in 1982 and the launch of the leprosy elimination strategy in 1991.³ This strategy proved highly successful in reducing the prevalence of cases of leprosy registered for treatment to below the target of one in 10 000 by the year 2000, but it had little effect on the rate of detecting new cases.⁴

Interest in the role of chemoprophylaxis was renewed by community interventions in Micronesia and studies of chemoprophylaxis in communities and household contacts in remote islands in Indonesia, where rifampicin was used instead of dapsone.^{5 6} As far as we know, Moet and colleagues’ trial is the largest randomised placebo controlled trial of chemoprophylaxis using rifampicin in household contacts of patients with newly diagnosed leprosy. It randomised 21 711 contacts of 1037 patients with leprosy to either a single dose of rifampicin in the second month after the patient started treatment or to placebo. Rifampicin significantly reduced the incidence of leprosy in the first two years (absolute risk reduction 57%, 95% confidence interval 33 to 72; number needed to treat 265, 176 to 537). However, the difference was no longer significant in the third and fourth years. The efficacy of a single dose of rifampicin is similar to that achieved by a much longer duration of treatment with dapsone (60% reduction).

This new evidence raises important questions—how can the efficacy of chemoprophylaxis be improved and what is the place of chemoprophylaxis in the global strategy against leprosy? In some cases, the absorption of rifampicin may have been adversely affected by a transient gastrointestinal illness (which is common in Bangladesh), so it is possible that the protection rate of 57% in Moet and colleagues’ trial could have been improved by giving a second dose the next day. Treatment of the index case prevents further transmission from that source but there may be other sources of infection in the vicinity that remain untreated, so a second dose in the future would reduce re-infection with Mycobacterium leprae. This would explain why chemoprophylaxis in whole communities is more effective than in household contacts.^{2 6}

BCG can help prevent leprosy, and it is used as immunoprophylaxis in household contacts in some South American countries.⁷ Moet and colleagues found the lowest risk of leprosy in household contacts who received rifampicin and who had previously been vaccinated with BCG. BCG stimulates the host’s immune response as opposed to killing M leprae so both treatments may act synergistically. Rifampicin cannot be given at the same time as BCG vaccination, however, because rifampicin would kill the BCG bacillus. Subgroup analysis in Moet and colleagues’ trial suggests that chemoprophylaxis is less effective in household contacts who are genetically related to the index case. This is relevant to recent research on the genetic basis of host susceptibility to M leprae infection; genetically related people may need a full course of multidrug treatment rather than a single dose of rifampicin.⁸

Most new cases of leprosy have no history of household exposure, which is not surprising given the very long incubation period. This limits the overall effect of a chemoprophylaxis strategy restricted to household contacts on the incidence of leprosy. Exposure to the leprosy bacillus outside the household will be limited in countries with good leprosy control programmes and a reduced burden of disease, which strengthens the case for routine chemoprophylaxis of household contacts in these situations. The acceptability of chemoprophylaxis in household contacts needs to be explored because—although newly diagnosed patients may welcome the opportunity to protect the rest of their household with single dose rifampicin—they are faced with disclosing a diagnosis surrounded by stigma. The development of a test for latent or subclinical infection with M leprae, such as a leprosy specific T cell assay with unique antigens selected from the genome, would complement chemoprophylaxis by identifying contacts at greatest risk.⁹

So what is the future role for chemoprophylaxis in the global strategy for leprosy after this new and robust trial? The current global strategy for leprosy for 2006-10 aims to sustain the control of leprosy and to reduce the burden of disease.¹⁰ The strategy does not recommend universal chemoprophylaxis, and this may need to be reviewed in light of the new evidence.¹¹ However, any changes should be considered on a country by country basis, rather than as part of the overall global strategy for leprosy, because the decision must be based not just on the efficacy of the intervention but also on feasibility, cost effectiveness, and acceptability.