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PREVENTION OF LEPROSY USING RIFAMPICIN AS CHEMOPROPHYLAXIS

ABSTRACT

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An intervention study was implemented on five Indonesian islands highly endemic for leprosy to determine whether rifampicin can be used as chemoprophylaxis to prevent leprosy. The population was actively screened before the intervention and subsequently once a year for three years. In the control group, no chemoprophylaxis was given. In the contact group, chemoprophylaxis was only given to contacts of leprosy patients and in the blanket group to all eligible persons. The cohort consisted of 3,965 persons. The yearly incidence rate in the control group was 39/10,000; the cumulative incidence after three years was significantly lower in the blanket group (P = 0.031). No difference was found between the contact and the control groups (P = 0.93). Whether this apparent reduced leprosy incidence in the first three years in the blanket group is due to a delayed development of leprosy or a complete clearance of infection needs to be determined.

INTRODUCTION

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Leprosy is an infectious disease caused by Mycobacterium leprae. Multidrug treatment (MDT) was introduced by the World Health Organization (WHO) in 1982 and was seen as an instrument for the elimination of leprosy as a public health problem, defined as a national prevalence less than 1/10,000.¹ However, even after 20 years of MDT, case detection rates (CDRs) are not decreasing,² indicating that patients are probably not the only source of transmission; subclinically infected persons and contacts of patients have also been implicated.^3,4 Therefore, it is necessary to examine interventions which include these groups of potentially infectious persons.

Vaccination with bacillus Calmette-Guérin has been shown to have varying efficacy (20–80%) against leprosy.⁵ In remote areas, chemoprophylaxis is operationally more feasible than vaccination, and among high risk groups it has been proposed as a strategy for lowering leprosy incidence.⁶ Chemoprophylaxis is already successfully used in some countries to prevent the spread of tuberculosis.⁷

Contact with a leprosy patient is thought to be the main determinant in incident leprosy. Similar to tuberculosis transmission,⁸ the "stone-in-the-pond" concept was suggested for describing leprosy transmission in concentric circles around a patient, whereby not only household contacts are at an increased risk of developing leprosy, but also neighbors and social contacts.⁹ Application of this concept in leprosy control would shift control activities from the current population-based approach to a more targeted approach for high risk groups.

In their meta-analysis, Smith and Smith⁶ have shown that chemoprophylaxis is an effective way to reduce the incidence of leprosy, and is more cost-effective when used in household contacts than in entire communities. Most chemoprophylaxis studies until now used dapsone and those few studies that did use rifampicin were non-controlled intervention studies.⁶ Therefore, it remains unclear whether rifampicin is effective as a chemoprophylaxis.

The objective of this study was to evaluate rifampicin prophylaxis as a preventive measure in leprosy control. We investigated whether prophylaxis used in contacts compared with whole communities is equally effective in preventing leprosy. We report here, to our knowledge for the first time, on a controlled community-based intervention study to determine which categories of contacts need rifampicin prophylaxis to obtain a reduction of clinical leprosy as measured by leprosy incidence.

METHODS

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Study population. From a 30-island archipelago in the Flores Sea in Indonesia, selected as the study area because of its geographic isolation and the absence of a routine leprosy control program, five islands were chosen by local health care officials based on their cooperation. A description of these islands was previously published.¹⁰ Prior to the study, we received ethical clearance from the Ethical Research Committee of the Hasanuddin University and from the Ministry of Health of the Republic of Indonesia. The community leaders of each of the islands gave written communal consent each year.

Study design. To form similarly sized intervention groups, three islands were combined into one intervention group. Two types of chemoprophylactic intervention strategies were compared with a control group. The blanket group included three islands on which prophylaxis was given to all eligible persons. The contact group included an island on which prophylaxis was given to all eligible contacts of all known leprosy patients in 2000. The control group was an island on which no chemoprophylaxis was given.

Assignment of the intervention strategies to the islands was based on predetermined criteria: 1) only islands where 20% of the population was a contact of a leprosy patient were eligible for contact intervention to show a clear distinction between the contact and blanket interventions; and 2) island(s) with highest CDR received the blanket intervention.

In both interventions, we used two doses of 600 mg of rifampicin for adults and 300 mg for children (6–14 years old) with approximately 3.5 months between doses. Children < 6 years of age, pregnant women, and persons with clinically observed liver failure or suspected tuberculosis did not receive prophylaxis. All leprosy patients were treated with the standard MDT directly after diagnosis.

The baseline and intervention phase took place in June–July 2000 (first survey) and October–November 2000 (second survey). The first survey consisted of a population census, preparation of detailed maps of all islands including all houses, and an active door-to-door screening for leprosy.¹⁰ At the end of the first survey, the first dose of chemoprophylaxis was supplied. During the second survey persons, who were missed during the first survey were examined and the second dose of rifampicin was supplied. We recorded whether the prophylaxis was taken under supervision or given via a close relative when the person was absent. During three yearly follow-ups (June 2001, April 2002, and April 2003) active door-to-door screenings for leprosy were repeated on all islands by the same research team.

Outcome measure. Leprosy was clinically diagnosed based on detailed skin examination, including testing for anesthesia and examination for enlargement of nerves, and confirmed by an experienced doctor. Classification was based on the WHO system of lesion counting (paucibacillary [PB] patients = 1–5 lesions, multibacillary [MB] patients = > 5 lesions).¹¹ Classification of PB patients was afterwards adjusted to MB when the outcome of the skin smear microscopy was positive.¹⁰

Definition of contacts. Contacts comprised household and neighbor contacts.⁹ Household contacts were persons who lived with a patient in the same household (house). Neighbor contacts were persons who lived either in a house adjacent to the patient’s house (neighbor 1) or in a house adjacent to a neighbor 1 house, in both cases with a distance of less than 50 meters between the houses. For all contact types, the duration of contact should have been at least six months and the contact should not have ended longer than six months prior to the baseline survey. The contact status in 2000 was used in the analysis.

Data analysis. The outcome measure was leprosy incidence. Only persons who were at risk for leprosy in July 2000 (i.e., persons screened in 2000 without leprosy) and who had followed the protocol (Figure 1) were included in the survival analysis. Persons not following the protocol (62) were those who received only one dose of rifampicin because they died or moved away, were wrongly defined as contacts in the contact group during the first survey, or were only identified as a contact of a patient found during the second survey. Persons who received one or no dose for other reasons such as pregnancy, and thus followed the protocol, were included in the analysis.

View larger version (37K): [in this window] [in a new window]       FIGURE 1. Trial profile. MDT = multidrug treatment.

Kaplan-Meier cumulative incidence curves of each group were compared with the log-rank test. It should be noted that the contact group consisted of both those who received prophylaxis (contacts) and those who did not receive prophylaxis (non-contacts). Cox proportional-hazards regression was used to independently estimate the effect of the different strategies and also the effect of prophylaxis regardless of the strategy calculating hazard ratios (HRs) and their 95% confidence intervals (CIs). In multivariate analysis sex, age (in categories), and contact status were added. We tested for interaction and confounding between covariates and performed stratified analysis for the different types of contacts. The proportionality assumption was satisfied for all covariates.

RESULTS

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In June 2000, 4,739 persons were living on the five islands. During the baseline surveys, 4,123 inhabitants were screened. A total of 3,965 persons were included in the cohort (Figure 1). The male:female ratio was 0.82 in the cohort and 2.4 outside the cohort. This difference was seen in all three groups. Relevant differences between the three intervention groups during the baseline survey were screening coverage and leprosy prevalence (Table 1). Due to the differences in leprosy prevalence, the percentage of contacts differed between groups. The migration rate during the study period also differed between islands.

During follow-up, 29 new leprosy patients were detected in the cohort: 11 in the control group, 15 in the contact group, and 3 in the blanket group (Table 2). Figure 2 shows the cumulative incidence for the different groups. The cumulative incidence after 33.5 months was significantly lower in the blanket group compared with the control group (P = 0.031, by log-rank test). No difference was found between the contact and control groups (P = 0.93).

View larger version (15K): [in this window] [in a new window]       FIGURE 2. Kaplan-Meier curves for cumulative incidence of leprosy for three different intervention strategies.

Table 3 shows the adjusted HRs for developing leprosy in the blanket and contact groups compared with the control group. There were no interactions between the covariates and intervention strategy. The effectiveness of blanket supply of prophylaxis based on the adjusted HR was 74.6% (95% CI = 5.4–93.2). The effectiveness increased to 90.9% (95% CI = 25.8–98.9) if only those persons in the blanket group who received at least one supervised dose of rifampicin were taken into account. The HRs were also calculated for the intake of prophylaxis regardless of intervention strategy. The adjusted HR in the population more than five years old for the intake of at least one supervised dose of rifampicin compared with no prophylaxis was 0.26 (95% CI = 0.078–0.86).

DISCUSSION

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Our findings are consistent with two previous blanket chemoprophylaxis studies that used dapsone rather than rifampicin. The studies were a large cluster randomized trial in India among persons less than 25 years old¹² and a controlled trial in Uganda among school children.¹³ Both showed a 99% protective effect that was much higher compared with the levels of protection found in household trials.⁶

Only one trial (non-controlled) has been reported to have used rifampicin prophylaxis (single dose of 25 mg/kg) in a blanket strategy in the southern Marquesas and concluded after 10 years of follow-up that the prophylaxis was 35–40% effective. They used previous CDR as historical controls correcting for CDR trends in the population that was not administered chemoprophylaxis.^14–16

The aim of chemoprophylaxis is to clear infection and interrupt transmission. The incubation period of leprosy lies in most instances between two and five years,¹⁷ but may be as long as 21 years.¹⁸ We therefore expect that the majority of the patients detected during the almost three years of follow-up were already infected before the intervention. Thus, chemoprophylaxis prevented the development of clinical signs in persons already infected with M. leprae. It is still uncertain whether this was a result of a lengthening of the incubation time or a complete clearance of infection. A longer follow-up time is needed to determine whether transmission was really interrupted in the blanket group.

We did not find a difference in the cumulative incidence after 33.5 months between the control and the contact groups. Based on our contact definition, 19% of the population in the contact group was defined as a contact of a leprosy patient and received prophylaxis. We defined contacts solely on spatial grounds; therefore, we may have missed important contacts such as social, work-related, and familial contacts. In the blanket group, all eligible persons received prophylaxis; thus, these other types of contacts were included in this intervention, which may be an explanation for the observed difference in effect of the two interventions. Another reason for not finding an effect of the contact intervention could be that within this area highly endemic for leprosy, everyone has contact with a leprosy patient. To measure the effect of prophylaxis in contacts, an intervention in an area with low disease endemicity may be needed with a much larger sample size since incidence rates will be low.

Stratified analysis showed that a lower incidence of leprosy was observed mainly among the non-contacts in the blanket group. This could be an explanation for the absence of an effect of the intervention in the contact group. What are possible reasons that prophylaxis was not working as effectively as expected among contacts? First, new patients may have arisen due to ongoing transmission among contacts after the intervention. Even if this is the case, it is doubtful that it would have an effect on the outcome since new patients were most likely already infected before the intervention. Second, more subclinical patients may be expected among the contacts since they have a higher risk of developing leprosy than non-contacts.^9,19 For these subclinical patients, two doses of rifampicin may not be enough to stop the development of clinical disease.

It was not feasible to blind the study because of logistic constraints. Knowing the allocation of the intervention strategies, the research team may have been tempted to screen the control group more and/or the intervention group less thoroughly. In that case, one would expect more single lesion (PB1) patients in the control group compared with the other groups because single lesions are easier overlooked during a less-detailed examination. However, we did not find differences in the incidence of PB1 patients between the three groups.

Since this was a community-based intervention study in which whole communities (with their intrinsic differences) were compared, differences between the control and intervention groups could introduce a bias. We do not expect large differences with respect to socioeconomic and health status, since the islands have the same income generating activities and rudimentary health care system. We assigned the blanket intervention to the island group with the highest prevalence to ensure that a lower incidence during follow-up would not be caused by an already lower initial prevalence.

Selection bias due to persons lost to follow-up may have influenced the estimated incidence in the groups. In all three groups, men and older persons were more often lost to follow-up. Only in the blanket group contacts were less often lost to follow-up. Contacts have an increased risk of developing leprosy compared with non-contacts,^9,19 and thus a possible effect would be a lower incidence in the blanket group and consequently a stronger effect of blanket chemoprophylaxis.

There are three potential sources of continuing transmission: 1) prevalent patients outside the cohort who were not detected in 2000, 2) patients who migrated to the islands, and 3) incident patients among persons lost to follow-up. Prevalent patients as well as migrated patients were only detected on the control and contact islands. The influence of this on the outcome of the study is expected to be very small since the patients detected during follow-up were most likely already infected before the intervention.

A limitation of the study is that it has been performed in a setting with a very high incidence of 39/10,000 per year in the control group. Whether a blanket approach also gives high effectiveness in an area with lower endemicity needs to be explored.

In conclusion, population-based prophylaxis was associated with a reduced leprosy incidence in the first three years after implementation. Prolonged follow-up will show if the intervention only causes a delay in the development of leprosy or a complete clearance of infection and interruption of transmission. We showed that in this area of high endemicity rifampicin prophylaxis for spatially defined contacts only does not influence leprosy incidence. Further studies including social contacts are needed to investigate the effect of prophylaxis given to contacts in areas of low endemicity.

Received October 8, 2004. Accepted for publication November 16, 2004.

Acknowledgments: We appreciate the permission and active support given by the manager and personnel of Health District Pangkep. We thank all people who were part of the research team: H. Hasan Basri, H. Baso Datu, H. Azis Nur, I. Nengah Sudja, Hj. Asriah, Mr. Saeni, Hj. Rabiah, Amril, Arief, Sufrianti, Syahuni, Romi Usman, Marwani, Syafri, and Mus Jebaru. We are grateful to all the inhabitants of the five islands (Sapuka Besar, Sailus Besar, Kembanglemari, Pelokang, and Tampaang) for their cooperation. We also thank Wim van Brakel, Pieter Feenstra, Jan Hendrik Richardus, and William Faber for critically reading the manuscript and giving their comments.

Financial support: This work was supported by the Netherlands Leprosy Relief.

Authors’ addresses: Mirjam I. Bakker, Birgit H. B. van Benthem, Stella M. van Beers, Paul R. Klatser, and Linda Oskam, KIT Biomedical Research, Koninklijk Instituut voor de Tropen/Royal Tropical Institute, Meibergdreef 39, 1105 AZ Amsterdam, The Netherlands, Telephone: 31-20-566-5450, Fax: 31-20-697-1841, E-mail: m.bakker{at}kit.nl. Mochammad Hatta and Agnes Kwenang, Department of Microbiology, Faculty of Medicine, Hasanuddin University, Kampus Tamalanrea KM 10, Jln. Perintis Kemerdekaan, Makassar, Indonesia.

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