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The efficacy of a four-week, ofloxacin-containingregimen compared with standard WHO-MDTin PB leprosy
M A R I V I C F . B A L A G O N * , R O L A N D V . C E L L O N A * ,R O D O L F O M. AB A L O S * , RO B E R T H . G E L B E R* *& PA UL R . SA UND ERSO N*
*Leonard Wood Memorial Center for Leprosy Research,
**University of California, San Francisco, USA
Accepted for publication 24 November 2009
To compare the efficacy of a 4-week ofloxacin-containing regimen and
the standard WHO-MDT regimen for PB leprosy, in terms of the rate and timing ofrelapse after treatment completion.
124 PB patients were enrolled in a randomised, double-blind trial. Of these,
66 received the standard 6-month WHO-MDT regimen, whereas 58 received 28 dailysupervised doses of rifampicin 600 mg þ ofloxacin 400 mg, plus 5 months ofplacebo. Patients were regularly monitored for clinical response and for signs ofrelapse after treatment completion.
Patients enrolled in the ofloxacin group had a mean follow-up of 10·8 years
(628 patient-years) with 1 early relapse at 3 years after treatment completion. Onrelapse, this patient remained smear negative but was reclassified by current WHOcriteria ($ 6 skin lesions) as multibacillary (MB). Patients on the WHO-MDTregimen had a mean follow-up of 11·3 years (749 patient-years) with two late relapsesat 8 and 12 years, both still classified as PB on relapse.
In conclusion, both regimens appeared generally efficacious, and, in
particular, resulted in few relapses.
For practical purposes in the field, leprosy patients have been classified into multibacillary(MB) and paucibacillary (PB) leprosy by the World Health Organization (WHO), since 1982.
PB leprosy is currently diagnosed when there are five or fewer leprosy skin lesions, whilemore than five lesions indicate MB leprosy. If a skin smear is done, any positive result meansan automatic classification as multibacillary, whatever the number of lesions. It has been
Correspondence to: Marivic F. Balagon, LWM Center for Leprosy Research, Cebu, Philippines, PO Box 727,
Cebu City, Philippines (Tel/fax: þ 63 32 2311601; e-mail: firstname.lastname@example.org)
reported that some PB patients may heal spontaneously, but if left untreated, a number ofthem may develop nerve complications and some may eventually become multibacillary(MB) cases.
The WHO Multiple Drug Therapy (WHO-MDT) for PB leprosy of 6 month duration has
performed well as to efficacy, acceptability and feasibility. However, some still consider the6 month treatment duration too long for such a mild disease and feel the need for a shorteralternative regimen.
Ofloxacin, as well as other quinolones, has been reported to have a rapid and highly
bactericidal activity against M. leprae in mice and in man and its addition to rifampicin, also ahighly bactericidal drug, is believed to result in a regimen that may shorten the requiredtreatment duration for PB leprosy.
To examine such reports, a multi-centre trial based on the TDR/THELEP protocol and
WHO/CIOMS guidelines was conducted. Its main objective was to find out whether a dailydose of rifampicin and ofloxacin given for 4 weeks would be as effective as the standardWHO-MDT regimen. This paper deals only with results of one centre, the Cebu Skin Clinic –a facility of the Leonard Wood Memorial Center for Leprosy Research (LWM), Cebu,Philippines.
A longitudinal, double-blind trial was conducted on previously untreated PB patients.
Patients with negative smears, who were classified clinically as either Indeterminate (I),Tuberculoid (TT) or Borderline Tuberculoid (BT), were eligible for enrollment. Patientsbetween 15 – 65 years old were recruited, sequentially enrolled and randomly allocated withpre-coded treatment regimens. The regimens used in the trial were the following:
WHO/MDT – PB regimen for 6 months (control)
rifampicin: 600 mg, supervised, monthlydapsone:
rifampicin 600 mg and ofloxacin 400 mg given in supervised doses dailyfor 4 weeks (followed by placebo until 6 months)
Potential participants were informed about the study. Those who agreed to participate wererequested to sign an informed consent form. Clinical and skin smear evaluation andmonitoring were done regularly at scheduled intervals before, during and after treatmentcompletion.
Comparing the therapeutic efficacy in terms of eventual regression of lesions and
occurrence of reversal reactions and relapses were among the parameters used in the study.
The study also sought to determine the feasibility of and tolerance to the newer drugcombination.
Relapse was the most important parameter in assessing the efficacy of the regimens and
was considered a critical issue in the trial. The possibility of relapse was considered if eitheror both of the following occurred:
A. The appearance of new skin and/or nerve lesion(s) – (not reactive lesions)B. BI of at least 2 þ at any single site
If only A was present, an independent assessor was requested to help assess the case. Biopsyfor histopathology was done. To confirm relapse, a therapeutic trial of corticosteroids wascarried out. The corticosteroid trial consisted of prednisone 40 mg daily for 2 weeks and then30 mg daily for another 2 weeks for a total of 4 weeks. If the new skin and/or nerve lesion(s)disappeared, the condition was considered to be a reversal reaction. Reversal reaction wasconsidered mild if there was only an increased erythema and localised swelling of existinglesions and was considered moderate to severe if this was accompanied by fever, malaise,edema, ulceration, appearance of new reactive lesions and/or neuritis.
In the absence of a clinical response to the corticosteroid trial, the case was considered a
relapse. When B was present, a case of relapse was immediately confirmed because of thepositive smear.
In our centre, a total of 124 PB patients were recruited between 1992 and 1994. These
patients were kept under surveillance until 2006.
C L I N I C A L P R O F I L E O F P A T I E N T S
A total of 124 PB patients were recruited and sequentially enrolled between 1992 and 1994.
On enrollment, patients were randomly allocated with pre-coded treatment packs. Of the124 patients, 66 were enrolled in regimen A (WHO-MDT) and 58 patients receivedregimen B (rifampicin-ofloxacin).
summarises the clinical profiles of all patients enrolled in the study.
L E P R O S Y T Y P E A N D N U M B E R O F L E S I O N S
demonstrate the clinical type and the number of lesions presented by thepatients. In both study groups, most of the patients were of the BT type and presented with
Table 2A. Lepros type and number of lesions: WHO-MDT (n: 66)
only one lesion. Although lesion count was not an inclusion criterion, it is noteworthy tomention that none of the patients in fact had . 5 lesions so the whole cohort will still beconsidered as PB under the current lesion count definition for PB leprosy.
C L I N I C A L C O U R S E O F L E S I O N S
shows the clinical course of the lesions of patients enrolled in both study groups.
In both groups, at 4 weeks, a majority of the patients had already responded clinically,
showing regression of the lesions. At 12 months, all patients in both treatment groups showedsignificant clinical response to treatment.
shows the incidence and severity of reversal reaction experienced by the patients.
Of the 66 patients in the WHO-MDT group (regimen A), only three (4·5%) had reversal
reactions and all were of mild severity. Of the 58 patients in the ofloxacin group (regimen B),seven (12%) had reversal reactions, two of which were considered moderate to severe. Mostresponded well to steroid treatment at 20 – 40 mg/day which was gradually tapered accordingto the clinical response.
Only one patient belonging to regimen B developed grade 2 deformity after treatment.
This patient showed a partial response to steroid treatment but was eventually lost to follow-up due to migration.
summarises the length of time the patients have been under surveillance until theconclusion of the study in 2006. Patients enrolled in Regimen A have been on follow-up for
No Cases Mild Mod – sev Total Reaction (%) No Cases Mild Mod – sev Total Reaction (%)
a total of 749 patient-years with a mean of 11·3 years. A total of 7 or 9·3% were lost to follow-up for varied reasons.
Patients enrolled in Regimen B have been on follow-up for a total of 628 patient-years
with a mean of 10·8 years. A total of 7 or 11·1% were lost for varied reasons.
Except for one patient in the rifampicin-ofloxacin group who complained of occasionalepigastric pain (not requiring the cessation of treatment) towards the later part of histreatment, both regimens were well tolerated by the patients.
Through 2006, a total of three relapses were detected. shows the clinical profile ofthese relapses – two from the WHO-MDT group which occurred 8 and 12 years aftertreatment and one from the ofloxacin group which occurred 3 years after treatment.
Among these patients, reversal reaction was ruled out and relapses were considered most
likely because of the absence of clinical response to therapeutic steroid trial. These relapseswere further confirmed histopathologically. In another patient who showed signs of a latereversal reaction, relapse was ruled out because of his clinical response to a therapeutic trialof steroids.
Note: Gap years (years elapsed from treatment completion to eventual relapse).
UE (upper extremity); LE (lower extremity); R (right); L (left).
ABI (average bacterial index).
This study shows that both regimens are safe and effective in the treatment of PB leprosy.
However, the ofloxacin-containing regimen seems to have an advantage in the field becauseof its shorter duration.
However, although small in number, relapses still occurred after both regimens. Of the
66 patients treated with WHO-MDT, two patients or 3% relapsed. Such relapses occurred verylate, at 8 and 12 years after treatment completion. On the other hand, of the 58 patients treatedwith the rifampicin-ofloxacin combination, only one patient or 1·7% relapsed. This patientrelapsed 3 years from treatment completion, much sooner than the relapses in the WHO-MDTgroup.
The late relapses observed in the MDT group could be due to a reactivated disease due to the
presence of persister organisms. Persister organisms lie dormant and/or are located ininaccessible tissues of the body such as the nerves. They are not affected by treatment becauseof their non-metabolising state or dormancy and/or because of their inaccessible location in thebody. Once treatment is stopped however, the organisms may start to multiply and eventuallyproduce a disease with organisms still sensitive to the drugs used earlier in the treatment of thecase. This may occur in some PB patients with borderline-tuberculoid type of leprosy whoexhibit some degree of anergy or partial suppression of their cell-mediated immunity toM. leprae. Under these circumstances, some persister organisms could survive until treatmenthas been stopped. However, re-infection in these particular cases is also a possibility.
The early occurrence of relapse observed in the ofloxacin group seems to suggest the
possibility of inadequate treatment. Irrespective of relapse definition, the issue as to whetherPB relapses in leprosy are due to inadequate treatment, drug resistance, re-infection or thereactivation of bacilli which have survived treatment remains irresolvable to date. In thiscase, however, the timely regression of lesions on re-treatment seems to rule out thepossibility of drug resistance, although this would still be difficult to confirm.
The fact that the relapse after the shorter, ofloxacin-containing regimen occurred early
and became multibacillary (defined as more than five lesions), although the skin smearremained negative, suggests that such treatment may have been inadequate. It has beenknown for sometime that this regimen has a high failure rate in multibacillary leprosy. On theother hand, the lack of early relapses in the WHO-MDT group may suggest its more effectivesterilising activity in paucibacillary cases.
In conclusion, both regimens are effective in treating PB leprosy. However, the
differences in the timing of relapse suggest that the shorter, ofloxacin-containing regimen ismaybe less effective in a small proportion of PB cases with a larger bacillary load.
This study was supported by a grant from the World Health Organization (UNDP/WorldBank/WHO Special Programme for Research and Training in Tropical Diseases).
Dr Tranquilino T. Fajardo Jr served as an independent assessor of patients with signs ofrelapse. Junie Abellana, Rico Abella, Mary Grace Bordon and Florenda Orcullo of theEpidemiology Branch (Cebu Skin Clinic) provided both technical and clerical assistance in thisstudy. Guillerma Lim, Bernardo Mendoza and Jay Vicada were also very helpful in providingadministrative support in the care and long term follow-up of patients included in this study.
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