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Tropical Medicine and International Health doi:10.1111/j.1365-3156.2011.02873.

volume 16 no 12 pp 15411551 december 2011

Systematic Review

Is there a role for rifampicin, ofloxacin and minocycline (ROM)


therapy in the treatment of leprosy? Systematic review and
meta-analysis
Maninder S. Setia1,5, Santosh S. Shinde2, Hemangi R. Jerajani3 and Jean-Francois Boivin4

1 Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada
2 Cutis Skin Clinic and Laser centre, Belgaum, Karnataka, India
3 Department of Dermatology and Venereology, M.G.M. Medical College and Hospital, Kamothe, Navi Mumbai, India
4 Clinical Epidemiology, Jewish General Hospital, Montreal, QC, Canada
5 Consultant Dermatologist and Epidemiologist, Karanam Consultancy, Mumbai, India

Summary background A combination of rifampicin, ofloxacin and minocycline (ROM) is one of the newer
recommendations for treatment of leprosy. We performed a systematic review and a meta-analysis of
studies that had evaluated the efficacy of ROM therapy in treatment of paucibacillary and multibacillary
leprosy patients.
methods Studies were identified by searching the PubMed, Embase, LILACS and Cochrane databases.
Data were abstracted from all relevant studies, and fixed effects models were used to calculate the
summary estimate of effect in paucibacillary and multibacillary leprosy patients.
results Six studies comparing ROM therapy to multidrug therapy and eight studies that evaluated the
effect of ROM therapy alone (no comparison group) were included in the review and meta-analysis. The
combined estimate for single dose ROM vs. multidrug therapy in paucibacillary leprosy patients sug-
gested that ROM was less effective than multidrug therapy in these patients [relative risk: 0.91, 95%
confidence intervals (CI): 0.860.97]. However, the combined estimate for multiple doses of ROM vs.
multidrug therapy in multibacillary leprosy patients suggested that ROM was as effective as multidrug
therapy in reducing bacillary indices in these patients (proportion change: )4%, 95% CI )31% to 23%).
No major side effects were reported in either the ROM or the multidrug treatment groups.
conclusions Single-dose ROM therapy was less effective than multidrug therapy in paucibacillary
patients. However, there are insufficient data to come to a valid conclusion on the efficacy of multidose
ROM therapy in multibacillary leprosy, and additional studies with ROM therapy in multibacillary
leprosy are needed. Furthermore, multiple doses may be considered as another alternative even for
paucibacillary patients, and randomised controlled trials of this therapy may be useful to understand its
contribution in the treatment and control of leprosy.

keywords rifampicin, ofloxacin and minocycline therapy, leprosy, systematic review

has initiated the leprosy elimination programme with the


Introduction
aim to reduce the prevalence of leprosy to less than one
Leprosy, a disease known since ancient times, continues to case per 10 000 population, so that it ceases to be a public
be a public health concern in many countries around the health problem in the world. Some of the important
world. World Health Organization (2010a) estimated that components of this elimination programme are knowl-
there were about 244 000 reported cases of leprosy edge and information about the diagnosis, prompt
globally in 2009. The majority of these cases were in Asia, diagnosis and effective treatment. (World Health Assembly
Africa and countries of South America. India alone, with 1991; World Health Organization 2010b).
133 717 reported cases, accounted for nearly 55% of the The treatment of leprosy has changed in the past three
global cases (World Health Organization 2010a). WHO decades. Dapsone monotherapy was replaced by multidrug

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Tropical Medicine and International Health volume 16 no 12 pp 15411551 december 2011

M. S. Setia et al. ROM therapy in leprosy: a systematic review and meta-analysis

therapy (with dapsone, rifampicin and clofazimine) in and ROM and Leprosy to identify these articles. The
1982 (World Health Organization 1982; Gautam 2009). search was not limited to English language articles, and we
Since its introduction, multidrug therapy has been an translated studies in other languages if required. Inclusion
important tool in leprosy elimination; not only has it criteria were established prior to identifying the articles to
helped to reduce the duration of treatment but it has also avoid any selection bias. All the studies that described the
been useful in addressing problems related to resistance to efficacy of ROM in treatment of leprosy in human subjects
dapsone and relapses (Ji 1998; Visschedijk et al. 2000; (leprosy diagnosed according to clinical and or microscopic
Meima et al. 2004) Indeed, WHO has been providing the criteria) were eligible for inclusion. We excluded studies
multidrug regimen free of cost for treatment of leprosy that assessed only changes in immunological status of
patients since 1995 (World Health Organization 2010c). individuals after ROM therapy, studies that did not describe
The current WHO recommendations for adults are as clinical improvement outcomes, case reports of ROM
follows: rifampicin (600 mg once a month), dapsone therapy and reviews of leprosy therapy. We also excluded
(100 mg daily) and clofazimine (300 mg once a month and studies that had used ROM in combination with other
50 mg daily) for 1 year for multibacillary leprosy; and treatments. Although these studies were excluded from the
rifampicin (600 mg once a month) and dapsone (100 mg meta-review, we read them to identify potentially eligible
daily) for paucibacillary leprosy for 6 months (World studies for our review and for the overall discussion on the
Health Organization 2010d). In addition to these medica- role of ROM therapy in leprosy. If a study had multiple
tions for cases of leprosy, studies have also highlighted the published reports, the report with the maximum number of
role of vaccines (such as BCG, Mycobacterium vaccae, and cases and longest duration of follow-up was included. A list
others) in the prevention of leprosy. (Talwar 1985; Fine & of all the studies (included and excluded) was maintained.
Dockrell 1991; Gupte 1991; Stanford 1994; Setia et al. Conference abstracts were not included.
2006; Schuring et al. 2009).
These multidrug therapy regimens have been very useful
Data abstraction
in treatment and control of leprosy. However, poor
compliance (related to long duration and other socio- Two major groups of studies were identified: those that
economic factors), drug resistance, and relapses have been compared ROM therapy with WHO multidrug therapy
reported (Gautam 2009). Thus, there has been a renewed (referred to as comparison studies in this manuscript) and
effort to find newer regimens that may shorten the duration those that reported the clinical efficacy in ROM only
of therapy and improve compliance while simultaneously (referred to as ROM only studies), without inclusion of a
maintaining or improving the therapeutic advantages of comparison group. For the comparison studies, we ab-
previous regimens (Sehgal et al. 2008). In 1997, a combi- stracted information on the authors, year of publication,
nation of rifampicin (600 mg), ofloxacin (400 mg) and place of study, the inclusion and the exclusion criteria, the
minocycline (100 mg) ROM therapy was approved design of the study (randomised controlled trial, non-
for single-lesion paucibacillary (PB) leprosy (WHO 1998). randomised study, procedure of randomisation if any,
In the late 1990s, there have been many studies of the use blinding procedures if any, allocation of the medications),
of ROM therapy and some of these have also included description of the intervention and control groups, the
multilesional paucibacillary leprosy and even multibacil- number of study participants in each group, duration of
lary leprosy, although a few authors have expressed some follow-up, the dose and duration of medications in each
reservations about this therapy (Lockwood 1997; Katoch group, the clinical, bacteriological, and or histopathologi-
1998; Lockwood & Kumar 2004). Thus, we conducted a cal criteria for monitoring the subjects, improvement in each
systematic review and a meta-analysis of these studies to group, the side effects, reactions and relapses in each group.
understand the utility of ROM therapy in leprosy. For the ROM only studies, we abstracted information on
authors, place of study, year of publication, study popula-
tion, treatment and follow-up, response to treatment, side
Methods effects, reactions and relapses. Two reviewers (MSS and
SSS) were primarily responsible for data abstraction.
Data sources
Unresolved issues were addressed by consulting JFB.
We performed a comprehensive literature search of the
PubMed, EMBASE, LILACS and Cochrane Database (up to
Data analysis and statistical methods
October 2010) to identify the studies that assessed the role
of ROM therapy in the treatment of leprosy. We used the Data for the paucibacillary and multibacillary leprosy
terms Rifampicin, Ofloxacin, Minocycline and Leprosy studies were analysed separately. We extracted the effect

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Tropical Medicine and International Health volume 16 no 12 pp 15411551 december 2011

M. S. Setia et al. ROM therapy in leprosy: a systematic review and meta-analysis

measure (relative risk RR) and its 95% confidence interval results closer to a null effect (Song et al. 2000) by using a
for clearance of lesions (as defined by the authors of the funnel plot; ln RR for each of the individual studies was
published papers) in the ROM group compared with the plotted against its SE. Further, publication bias was
standard therapy group. For manuscripts without RRs, we evaluated using Beggs (Begg & Mazumdar 1994) and
calculated them using the raw data (numbers treated healed Eggers tests (Egger et al. 1997). We used Stata version 10
etc.) provided by the authors. We calculated the pooled (StataCorp, College Station, TX, USA) for these tests and
summary of these RRs using fixed effects models as the Forest plot.
described by Greenland (1987). For each study, the standard
error (SE) of the RR was calculated by dividing the Results
difference in natural logs of the upper and lower confidence
Search results: included and excluded studies
limits by 3 92 (i.e., SE = [ln CIupper ) ln CIlower] 3 92). The
inverse of the square of this standard error (1 SE2) was used We reviewed 257 citations identified from all the four data
as the weight (Wa) for pooling of the RRs. The summary bases. Details of the search are provided in Figure 1. After
measure was calculated by multiplying this weight by the excluding the duplicate citations and studies that were not
natural log of the RR (ln RRa). The sum of all the weighted directly relevant to this meta-analysis, we assessed 27
P
ln RRs was calculated ( Waln RRa). The pooled summary potential studies in detail. Of these, we excluded 13
P P
estimates was then calculated as Waln RRa Wa, and the studies: eight were additional reports of included studies
summary RR was obtained by exponentiating this pooled (Babu et al. 1997; Ganapati et al. 1999; Pai et al. 1999;
summary. We drew a Forest plot of all the studies included Gupte 2000; Martelli et al. 2000; Costa et al. 2001;
in the meta-analysis. We used methods described by Altman Emmanuel & Gupte 2005; National Institute of Epidemi-
and Bland (2003) to compare RRs and their respective ology 2005); two studies did not discuss response to ROM
confidence intervals (as was the case in sensitivity analyses). therapy (Revankar et al. 2002; Sousa et al. 2007); one
We could not calculate the RRs for multibacillary study was on contacts of leprosy patients who used ROM
leprosy studies; the two included studies only provided used as chemoprophylaxis (Oo et al. 2008); one study used
mean bacillary indices (BI) for the duration of follow-up. ROM along with the Convit vaccine (Majumder et al.
Thus, we calculated the proportion difference in BI 2000); and one study had initially compared ROM therapy
reduction between the ROM and the multidrug therapy with a combination of ofloxacin and minocycline for a
groups. We calculated the difference in mean BI at baseline week followed by standard multidrug therapy in all
and at 2 years in the ROM group (DR = Rb ) R2); the patients (Ji et al. 1998).
proportion difference was then calculated as PR = DR Rb. Thus, we included 14 studies for the review: six studies
Similarly, the proportion difference was calculated for the comparing ROM therapy with multidrug therapies
multidrug therapy group (PM). The overall difference in (Single-lesion Multicentre Trial Group 1997; 23 Lesion
proportion between the ROM and the multidrug therapy Multicentre Trial Group 2001; Deshmukh et al. 2003;
group was calculated as PR ) PM. We also calculated the Villahermosa et al. 2004; Gupte 2006a; Ura et al. 2007)
95% confidence intervals for this difference. The estimates and eight studies that observed the improvement only in
from the two multibacillary studies were pooled using the ROM therapy (there was no comparison group) (Mane
fixed effects approach (Cooper & Hedges 1994; Shams et al. 1997; Ebenezer & Job 1999; Revankar et al. 1999;
et al. 2010). We did not pool the data from ROM only Shinde et al. 2000; Shukla et al. 2002; Martelli et al. 2003;
studies; these were just described in the text and tables. Gupte 2006b; Alam et al. 2007).
The studies were also assessed for heterogeneity by using
the chi-square test with degrees of freedom equal the
Comparison studies (ROM vs. MDT)
number of studies that were combined in the meta-analysis
minus one. We planned to use the random effects model if Of the six comparison studies, four were conducted in
the studies were found to be heterogeneous. We also paucibacillary leprosy patients (Single-lesion Multicentre
assessed the quality of trials by criteria suggested by Jadad Trial Group 1997; 23 Lesion Multicentre Trial Group
et al. (1996); the trials are scored on the basis of descrip- 2001; Deshmukh et al. 2003; Gupte 2006a) and two
tion of randomisation, blinding and withdrawals. were conducted in multibacillary leprosy patients
(Villahermosa et al. 2004; Ura et al. 2007). The former
four studies used a single dose of ROM, whereas the latter
Publication bias
two studies used multiple doses. All four paucibacillary
We assessed publication bias because of the reluctance of leprosy studies were conducted in India. Of these, only one
authors and editors to publish smaller studies or those with study (Deshmukh et al. 2003) found a higher proportion of

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M. S. Setia et al. ROM therapy in leprosy: a systematic review and meta-analysis

Figure 1 Figure showing the data


abstraction procedure for the present
meta-analysis.

improvement in the ROM group than in the standard patients in both groups were too small to make any useful
multidrug therapy. The two studies in multibacillary conclusions. The other MDT-MB study by Ura et al.
leprosy patients found that multidrug therapy was slightly (2007) did not give any detailed information on the
more effective in reducing the bacillary index, although the reactions. One study in paucibacillary leprosy patients,
difference was not statistically significant. No life-threat- however, found that the relapse rate was twice as high in
ening side effects were reported in either of the groups; nor the ROM group as in the control group (multidrug
did there appear to be a preponderance of side effects in therapy) (Gupte 2006a). Tables S1 provides further details
either of the groups. Reversal reactions and erythema on each study.
nodosum leprosum reactions were reported in both.
Although one study found similar numbers of reactions in
ROM only studies
both the study (ROM) and the control (MDT-MB) groups
(Villahermosa et al. 2004), another (Single-lesion Multi- Of the eight studies in the ROM only group, five were
centre Trial Group 1997) found that the ROM group had conducted in India (Ebenezer & Job 1999; Revankar et al.
double the number of reaction cases as the MDT-PB group. 1999; Shinde et al. 2000; Shukla et al. 2002; Gupte 2006b)
Interestingly, although the former study provided detailed and one each was conducted in Brazil (Martelli et al. 2003),
information on reactions (Tables S1), the numbers of Bangladesh (Alam et al. 2007) and Senegal (Mane et al.

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Tropical Medicine and International Health volume 16 no 12 pp 15411551 december 2011

M. S. Setia et al. ROM therapy in leprosy: a systematic review and meta-analysis

1997). All but one (Mane et al. 1997) were in paucibacillary


Summary estimates and publication bias
leprosy patients. The effects in these studies were measured
by various criteria: clearance of lesions, disappearance of We calculated the RRs in four studies (Single-lesion Mul-
patches or reduction in granulomas on histopathology. ticentre Trial Group 1997; 23 Lesion Multicentre Trial
Overall, the range of clearance (as defined by the individual Group 2001; Deshmukh et al. 2003; Gupte 2006a) that
authors) for single-dose ROM therapy in paucibacillary compared single-dose ROM therapy to multidrug therapy in
leprosy patients varied from 44% in the study by Shukla paucibacillary leprosy patients. The summary estimate of
et al. (2002) and 99% in the study by Revankar et al. these RRs using the fixed effects model was 0.91 (95% CI:
(1999). Mane et al. (1997) had treated paucibacillary 0.860.97). No statistically significant heterogeneity was
patients with monthly doses of ROM for 6 months; they observed in these studies; hence, the random effects model
reported that about 25% of these patients had complete was not used. Figure 2a shows a Forest plot of individual
clearing of lesions and in the remaining subjects these lesions estimates and the combined estimate in the Forest Plot.
were reduced significantly. Although the majority of the There was no apparent publication bias as determined with
reports did not mention side effects, Mane et al. (1997), Beggs Funnel Plot (Figure 2b). The test for publication bias
who did specifically mention side effects, did not find any was not statistically significant by both Beggs and Eggers
clinical toxic effect of the medications. The highest rate of methods. Two studies (Villahermosa et al. 2004; Ura et al.
relapse was 6 1000 person years in the study by Revankar 2007) assessed the effect of multiple doses of ROM therapy
et al. (1999); however, this figure included delayed clinical in multibacillary patients. The combined proportion dif-
problems in relapses. Interestingly, Martelli et al. (2003) ference for the reduction in bacillary index in the ROM
from Brazil found that individuals who were positive for group compared with the multidrug therapy group in these
Mycobacterium leprae confirmed by PCR were more likely multibacillary leprosy patients was )4% (95% CI: )31% to
to report neural aggression. Further details on each study 23%). Both studies were statistically homogenous; hence,
are provided in Tables S2. the random effects model was not used.

Figure 2 (a) Forest plot of the


paucibacillary leprosy studies included in
the meta-analysis. The black dots are the
point estimates for each study and the
horizontal lines around it are the confidence
intervals. The box represents the size given
to each study in the fixed effects model
(mentioned as % Weights). The dashed line
is the combined estimate. The diamond
represents the confidence interval of the
summary estimate. (b) Funnel plot of all the
included studies in the meta-analysis
(assessing the publication bias).

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M. S. Setia et al. ROM therapy in leprosy: a systematic review and meta-analysis

and in a subsequent study found rifampicin to be highly


Sensitivity analysis
bactericidal compared with other regimens including
We performed sensitivity analyses on our results. For newer drugs. Unsurprisingly, rifampicin was thus included
instance, we had included data from a WHO report (Gupte in the multidrug therapy regimen for leprosy. However, it
2006a) on the effect of ROM therapy (compared with data was only in the latter half of 1980s that reports on the
from articles published in peer reviewed journals) in bactericidal effects of the other two drugs (ofloxacin and
paucibacillary leprosy patients in the meta-analysis. After minocycline) were discussed in literature; these reports
excluding this WHO report, we found that the summary included both animal studies and studies of clinical cases
estimate changed slightly (RR: 0.87, 95% CI: 0.790.96), of leprosy (Saito et al. 1986; Gelber 1987; Pattyn 1987;
even though this difference was not statistically significant Grosset et al. 1988, 1990; Leysen et al.1989; Franzblau
(P = 0.44). In one of the paucibacillary leprosy studies & White 1990; Gelber et al. 1992, 1994). In 1998, Ji
(Deshmukh et al. 2003), we used the number of patients et al. reported that although both combinations oflox-
that had clinically improved (compared with complete acin and minocycline & rifampicin, ofloxacin and mino-
clearance in other studies). The summary estimate after cycline were bactericidal, the former was less so than
excluding this study was nearly similar to the overall the latter in lepromatous patients. Hence, these animal
estimate (RR: 0.91, 95% CI: 0.860.97). and clinical studies demonstrated the role of these three
drugs in the treatment of leprosy; subsequently, clinical
studies were conducted to assess the efficacy of this com-
Discussion
bination in various forms of leprosy. However, Katoch
The present systematic review and meta-analysis present (1998) had reservations about the use of ROM in leprosy;
information on the role of ROM therapy in the treatment he argued that as Mycobacterium leprae does not multiply
of leprosy. Of the studies included for the systematic simultaneously, the use of these regimens may not have a
review, six compared ROM therapy to the multidrug convincing enough microbiological rationale for the use
therapy and eight studied the effectiveness of ROM of these regimens.
therapy alone. The combined estimate for single-dose As seen in our review, the two main groups of studies
ROM vs. multidrug therapy in paucibacillary leprosy that formed a part of the existing literature were as
patients suggested that ROM was less effective that follows: those comparing ROM therapy to multidrug
multidrug therapy in these patients (RR: 0.91, 95% CI: therapy and those that had simply evaluated the efficacy of
0.860.97). However, the combined estimate for multiple ROM therapy in treatment of leprosy patients. Interest-
doses of ROM vs. multidrug therapy in multibacillary ingly, even though WHO guidelines recommend ROM
leprosy patients (proportion change: )4%, 95% CI: )31% therapy for single-lesion paucibacillary leprosy
to 23%) did not provide enough information to substan- patients (World Health Organization 2010d), these stud-
tially conclude on the efficacy of multidose ROM therapy ies had used ROM in such patients (even with more than
in multibacillary leprosy and additional studies with ROM one patch) and in multibacillary leprosy patients; thus,
therapy in multibacillary therapy are needed. No major they are useful to understand the role of this therapy in
side effects were reported in either the ROM or the MDT different forms of leprosy. As observed in our meta-
treatment groups. analysis, single-dose ROM therapy was less protective
Even though the ROM regimen was recommended only than the WHO multidrug therapy in paucibacillary leprosy
in 1997, many previous clinical and animal studies had patients. In all of these studies, patients in the ROM group
suggested the utility of these medications in leprosy. received only a single dose of ROM therapy even though
Indeed, some studies in the 1970s demonstrated the the number of lesions varied from 1 to 5 among these
bactericidal effect of rifampicin on Mycobacterium leprae. patients. In contrast to this, all multibacillary leprosy
Rees et al. (1970) demonstrated that rifampicin inhibited patients received monthly doses of ROM therapy for
the growth of Mycobacterium leprae in mice; this 24 months; this was the same time period for which the
inhibition was seen in both dapsone sensitive and resistant control group received WHO multidrug therapy. As such,
bacilli. In the same study, rifampicin in a dose we found that the combined proportion change of bacil-
600 mg day was effective in treating lepromatous lary index was )4% (95% CI: )31% to 25%). The
patients. Subsequent studies in humans and animal confidence intervals were too broad, and sufficient increase
models confirmed the role of rifampicin in treating in statistical power was not achieved in multibacillary
leprosy. (Shepard et al. 1971, 1972, 1974; Levy et al. leprosy. Hence, there are insufficient data to conclude on
1976). Ji et al. (1992, 1996) initially reported that the efficacy of multidose ROM therapy in multibacillary
rifampicin was highly bactericidal even in a single dose leprosy, and additional studies with ROM therapy in

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M. S. Setia et al. ROM therapy in leprosy: a systematic review and meta-analysis

multibacillary leprosy are required. It appears that multi- with 25 lesions and treated with ROM were twice as
ple doses of ROM therapy are as effective as multidrug likely to have a relapse compared with those that were
therapy compared with single dose; we have to highlight, treated with WHO multidrug therapy. Thus, this appears
however, that these two different types of doses were used to be one shortcoming of ROM therapy. However, as
in different types of leprosy. Lockwood and Kumar (2004) pointed out, we need long-
The other group of studies, i.e., those that included term studies (follow-up of 10 years or more) for a better
only the ROM therapy group, also showed a clinical understanding of these phenomena. Finally, cost is another
improvement in the patients, although the proportion important factor to be considered when recommending
varied across different studies. All but one study had used this treatment. Villahermosa et al. (2004) reported that
ROM as a single-dose therapy for treatment of pauciba- ROM is more expensive than the WHO multidrug therapy
cillary leprosy patients. The study by Mane et al. (1997) for a similar duration of treatment, at least in the
from Senegal had used multiple doses of ROM once a Philippines. This trend may be expected in other countries
month for 6 months in paucibacillary leprosy patients and as well.
for 24 months in multibacillary patients and found As with other reviews and meta-analyses, the present
good clinical response among these paucibacillary leprosy study also has its limitations. Heterogeneity among studies
patients. Revankar et al. (1999) used single-dose therapy is an important limitation in most meta-analyses. As such,
in both single-lesion and multilesional (two to five lesions) different study sites and populations, varying study designs
paucibacillary leprosy patients; they reported nearly and procedures, and differences in measurements of
similar clinical outcomes in both these groups. Interest- clinical outcomes (complete clearance vs. clinical
ingly, one study (Alam et al. 2007) in this group had a improvement) may lead to heterogeneity between the
long average follow-up of 6.3 years (as reported to us by subjects. The type of medication used (for example, if
one of the co-authors of the study), and the authors generic versions vs. proprietary versions of the drugs are
reported a high relapse rate (5.09 per 1000 person years). used in these studies) may also contribute to the hetero-
Even though this study did not include comparison geneity. This heterogeneity can be accounted for by using
groups, the findings are useful to understand the clinical the random effects models as described by DerSimonian
outcomes in leprosy patients and for the design of future and Laird (1986). In our meta-analysis, we did not find any
studies. statistical heterogeneity between the paucibacillary leprosy
ROM therapy has its own advantages; it is administered studies or the multibacillary leprosy studies; thus, we
as single dose (or multiple doses every month) and may restricted our analyses to fixed effect models only. There
lead to better patient compliance, an issue that has been was, however, heterogeneity in the paucibacillary leprosy
highlighted as one problem of the WHO multidrug therapy study populations. Even though they were all paucibacil-
regimen (Gautam 2009). Another socially relevant lary leprosy patients, the number of lesions varied across
advantage discussed by Villahermosa et al. (2004) is the these studies. Furthermore, some studies had reported
pigmentation because of clofazimine in the multidrug complete clearance whereas another had just reported
therapy. They suggest that as none of the medications in clinical improvement.
the ROM therapy will cause the type of pigmentation Another important limitation of such analyses is the
associated with clofazimine, ROM will help maintain the potential publication bias because of the reluctance of
anonymity of these patients. Indeed, this was also high- authors and editors to publish smaller studies or those with
lighted by a WHO report on treatment of leprosy (WHO results closer to a null effect. (Song et al. 2000) We did not
1998). Even though individually each of these medications find evidence of publication bias in the funnel plot; there
rifampicin, ofloxacin, and minocycline may have side was no apparent asymmetry in the distribution of the four
effects including some very severe ones (Halkin 1988; Ji studies in this plot. Similarly, in the corresponding
et al. 1993, 1994; Vijayakumaran et al. 1997; WHO 1998; statistical tests, we did not find any evidence of publication
Namisato & Ogawa 2000), severe reactions were not bias. However, only four studies were available to assess
observed in the included studies. this bias.
Another important aspect of leprosy therapy is the rate Another important limitation to be considered in the
of relapses in treated patients. Although relapses were not present analysis is the bias in each of the individual studies.
mentioned in some of the included studies, many had Although some of the paucibacillary leprosy trials had
evaluated these in their study populations. The study with randomised treatment allocations, the methods of ran-
a relatively longer average follow-up period reported a domisation were not clearly specified in three of these trials
relapse rate of 5.09 per 1000 person years (Alam et al. (Single-lesion Multicentre Trial Group 1997; Deshmukh
2007). Others have reported that paucibacillary patients et al. 2003; Gupte 2006a) Furthermore, double blinding

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M. S. Setia et al. ROM therapy in leprosy: a systematic review and meta-analysis

was not clearly defined in the manuscripts of these trials. In


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online version of this article:
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Table S1. Publication details, Inclusion exclusion cri-
Song F, Eastwood AJ, Gilbody S, Duley L & Sutton AJ (2000)
Publication and related biases. Health Technology Assessment teria, description of study population, findings, side
4, 1115. effects reactions relapses and other characteristics of the

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Tropical Medicine and International Health volume 16 no 12 pp 15411551 december 2011

M. S. Setia et al. ROM therapy in leprosy: a systematic review and meta-analysis

studies that compared ROM therapy with standard WHO Please note: Wiley-Blackwell are not responsible for the
therapy. content or functionality of any supporting materials
Table S2. Description (place of study, study population supplied by the authors. Any queries (other than missing
and treatment, outcomes and relapses) of the observational material) should be directed to the corresponding author
studies using ROM therapy in the treatment of leprosy. for the article.

Corresponding Author Maninder Singh Setia, Consultant Dermatologist and Epidemiologist, Karanam Consultancy,
Ground Floor-66, Hi Life P M Road, Santacruz West Mumbai - 400 054, India. E-mail: maninder.setia@karanamconsultancy.in

2011 Blackwell Publishing Ltd 1551