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INTERNATIONAL JOURNAL OF LEPROSY^ Volume 62, Number 3Printed in the U.S.A.

Relapse Rates in Patients Treated with DapsoneMonotherapy and Combinations of Dapsone and

Thiambutosine, Thiacetazone, Isoniazid andStreptomycin in the Pre-MDT Era'

Trevor C. Smith and Jan Hendrik Richardus 2

Dapsone (DDS) was introduced as anti-leprosy treatment at the end of the 1940s.It was generally very successful, and DDSmonotherapy remained the mainstay of lep-rosy treatment until 1982 when the WorldHealth Organization (WHO) advised intro-ducing multidrug therapy (MDT) ( 9). Overthe years several problems had arisen withdapsone. In the first place it was found thatcertain people could not tolerate the drug,usually because of hypersensitivity to sul-fones. Also, resistance of the leprosy bac-teria to DDS became more frequent; manycases relapsed, often many years after com-pleting treatment. These problems neces-sitated the search for and introduction ofalternative antileprosy drugs. Eventually thisled to the recommendation by the WHO touse MDT. In MDT, dapsone is combinedwith rifampin in paucibacillary (PB) cases,and with rifampin and clofazimine in mul-tibacillary (MB) cases.

In order to assess the efficiency of thepresently used treatment schedules, it is im-portant to have insight into the results ofpast treatment schedules. In this paper theresults of three decades of dapsone mono-therapy are analyzed, with reference to re-lapse rates in both PB and MB patients.Also, a similar analysis will be done forcombination therapies given before theMDT era. Combinations that were re-viewed include dapsone with the followingdrugs: thiambutosine, thiacetazone, isoni-azid and streptomycin.

I Received for publication on 22 December 1993;accepted for publication in revised form on 28 April1994.

2 T. C. Smith, M.B.B.S.; J. H. Richardus, M.D., Ph.D.,McKean Rehabilitation Center, P.O. Box 53, ChiangMai 50000, Thailand.

MATERIALS AND METHODSAll leprosy patients included in this study

were treated at McKean RehabilitationCentre or associated clinics. The center islocated in Chiang Mai, northern Thailand.It is a church-related institution, servingleprosy sufferers since 1908. Until 1970 therewas a large colony with approximately 1000inpatients. Apart from the colony residents,many more people were treated as outpa-tients. Most patients originated from north-ern Thailand, but some came from otherparts of the country.

Dapsone monotherapy was started in1949. MDT, as advised by the WHO, wasintroduced in 1982. Between 1957 and 1982a number of alternative antileprosy drugswere used including Rimifon (INAH), thi-acetazone (TB1), thiambutosine (CIBA1906) and streptomycin. These drugs wereusually introduced when patients were con-sidered "intolerant" to dapsone. In practice,this meant that the patient was undergoinga leprosy reaction, usually type 2 (erythemanodosum leprosum, ENL). Dapsone was in-terrupted and the alternative drug was givenfor a period of time. Often dapsone wasresumed at a later stage. Thus usually se-quential (not combined), multidrug therapywas received by a number of the patients.It is appreciated that sequential monother-apy does not allow synergistic activity be-tween drugs, but on many occasions therewas overlapping of drugs for 1 to 3 months,especially when DDS was being re-intro-duced, and isoniazid and streptomycin wereusually given together. The DDS dosageregimens used since 1949 at McKean Re-habilitation Centre have been publishedelsewhere (').

All patients who started dapsone between1949 and 1976 were reviewed. Patients who

353

354^ International Journal of Leprosy^ 1994

TABLE 1. Relapse figures in paucibacillary patients on dapsone monotherapy between1949 and 1976 by sex and regularity of treatment.

Male Female Total

Reg:' (PYR) 0 Irr.' (PYR) Reg. (PYR) Irr. (PYR) Reg. (PYR) Irr. (PYR)

No relapse 375 (4895) 361 (5251) 190 (2643) 178 (2726) 565 (7538) 539 (7977)Relapse 12 (103) 23 (275) 1 (3) 7 (73) 13 (106) 30 (347)

Total 387 (4998) 384 (5526) 191 (2646) 185 (2799) 578 (7644) 569 (8325)

Relapserate per1000 PYR 2.4 4.2 0.4 2.5 1.7 3.6

Reg. = Regular (taking >70% of recommended dose).PYR = Person-years at risk.Irr. = Irregular (taking <70% of recommended dose).

were treated with dapsone monotherapyonly and patients who were treated withdapsone combined with at least one of theabove-mentioned drugs given for at least 3months were included. In the analysis ofmonotherapy, both PB and MB cases wereincluded. In the analysis of combined ther-apy, only MB cases were taken into consid-eration.

Patients selected for analysis needed tohave completed at least 3 years of dapsonemonotherapy if they belonged to the PBgroup (TT and BT with negative skin smearat presentation). Patients belonging to theMB group (BT with positive skin smear atpresentation, BB, BL and LL) needed to havetaken dapsone only or dapsone and the al-ternative drug until they became skin-smearnegative (defined as having a negative skinsmear on three consecutive examinationswith at least a 3-month interval). These pe-riods are referred to as the "treatment" pe-riod.

After the treatment period, an "obser-vation" period commenced for the calcu-lation of person-years at risk (PYR). Duringthis period most patients continued dap-sone monotherapy according to the then ex-isting guidelines. To differentiate in the de-gree of therapy compliance, a distinctionwas made between regular users (taking>70% of prescribed therapy) and irregularusers (taking <70% of prescribed therapy).The observation period was discontinuedwhen: the patient died; was lost for followup; started MDT; relapsed or reached theend of the study period (1991).

Relapse was defined as: a) the reappear-ance of a positive bacterial index (seen twice

with at least a 6-month interval) after atleast 3 years of skin-smear negativity, com-bined with new clinical activity in skin ornerves; and b) the reappearance ofnew, clin-ical lesions (even with skin-smear negativ-ity) after an adequate course of therapy.

The relapse rate was calculated by divid-ing the total number of relapses by the totalof person-years of observation (PYR).

RESULTSOf the 2296 patients treated with dapsone

monotherapy, 1147 belonged to the PBgroup and 1149 to the MB group.

Table 1 shows the figures for the PB group.A total of 43 patients relapsed during anaccumulated observation period of 15,969years (PYR), giving an overall relapse rateof 2.7 per 1000 PYR. The relapse rate amongpatients who took dapsone regularly was 1.7per 1000 PYR; among the irregular usersthis figure was 3.6 per 1000 PYR, the dif-ference being significant ( p < 0.05). Relapserates in males were 2.4 (regular) and 4.2(irregular) per 1000 PYR. In females theserates were 0.4 (regular) and 2.5 (irregular)per 1000 PYR. The difference between reg-ular males (2.4) and regular females (0.4) issignificant (p < 0.05). The relapse rate be-tween irregular males and females is notsignificant.

Table 2 summarizes the results for MBpatients treated with dapsone monothera-py. In this group there were 150 cases withrelapse observed during an accumulatedperiod of 14,297 years, giving an overall re-lapse rate of 10.5 per 1000 PYR. The re-lapse rate among patients who took dapsoneregularly was 9.9 per 1000 PYR; among the

62, 3^Smith and Richardus: Relapse Rates in Pre-MDT Era^355

TABLE 2. Relapse figures in multibacillary patients on dapsone monotherapy between1949 and 1976 by sex and regularity of treatment.

Male Female Total

Reg.° (PYR)b Irr. 0 (PYR) Reg. (PYR) Irr. (PYR) Reg. (PYR) Irr. (PYR)


Total 315 (3791) 503 (6377) 147 (1769) 184 (2360) 462 (5560) 687 (8737)Relapse

rate per1000 PYR 9.8 12.5 10.2 6.4 9.9 10.9

° Reg. = Regular (taking >70% of recommended dose).b PYR = Person-years at risk.

Irr. = Irregular (taking <70% of recommended dose).

irregular users this figure was 10.8 per 1000PYR. Relapse rates in males were 9.8 (reg-ular) and 12.5 (irregular) per 1000 PYR. Infemales these rates were 10.2 (regular) and6.4 (irregular) per 1000 PYR. There wereno significant differences between males andfemales and no significant differences be-tween regular and irregular patients.

Table 3 shows the results found in MBpatients who had been treated with dapsonetogether with an alternative drug. The al-ternative drug was taken for an average du-ration of 1.5 years (3 months to 15 years).The number of relapses observed in thisgroup is 34, seen during an accumulatedperiod of 1904 years. The overall relapserate is 17.9 per 1000 PYR. The differencein relapse rate in regular users (15.0) andirregular users (19.6) is not significant (p >0.05). The difference between regular males(13.8) and irregular males (22.1) is signifi-cant (p < 0.05). The difference between reg-ular (17.9) and irregular (12.8) females is

not significant. There are no significant dif-ferences between regular males and femalesand no significant differences between ir-regular males and females.

Comparing the PB and MB groups of pa-tients who had received dapsone monother-apy, there is a highly significant differencebetween the two groups. Between the groupsof MB patients who had received eithermonotherapy or combined/sequential ther-apy, the difference in the overall relapse rateper 1000 PYR and between the regular usersis not significant. The difference between theirregular users is significant, the combina-tion therapy group showing a higher relapserate.

Table 4 gives the leprosy classification asoriginally seen at the time the patient firstpresentated and at the time when the relapseoccurred.

The Figure shows the percentage of re-lapse per year of observation for the PB andMB groups. It is noted that in both groups

TABLE 3. Relapse figures in multibacillary patients who were treated with dapsonetogether with thiambutosine, thiacetasone, isoniazid or streptomycin between 1949 and1976 by sex and regularity of treatment.

Male Female Total

Reg.° (PYR)b Irr.c (PYR) Reg. (PYR) Irr. (PYR) Reg. (PYR) Irr. (PYR)


Total 42 (509) 72 (859) 20 (224) 26 (312) 62 (733) 98 (1171)Relapse

rate per1000 PYR 13.8 22.1 17.9 12.8 15.0 19.6

° Reg. = Regular (taking >70% of recommended dose).b PYR = Person-years at risk.

Irr. = Irregular (taking <70% of recommended dose).


10^15^20^25^30

Year of observation

THE FIGURE. Percent relapses per year of obser-vation. = Multibacillary; —+— =paucibacillary.

50% relapsed after the seventh year of ob-servation.

DISCUSSIONThe main features of this study, com-

pared to most previous studies, are the longperiod of observation after completing thetreatment period and the inclusion of thegroup of patients who had received a com-bination of antileprosy drugs in the pre-MDT era. The main difference with manysimilar studies is the fact that the group ofpatients included in this study continued touse dapsone during their observation peri-od.

In the PB group, the overall relapse rateover an average observation period of 13.9years (1-30 years) was 2.7 per 1000 PYR(3.7% of the total group). Jesudasan, et al.observed a relapse rate in 1701 PB patientsduring a 3-year period of follow up of 9.7per 1000 PYR (4). A relapse rate of 7.2 per1000 PYR over an average period of 6.6years was found by Becx-Bleumink ('). Pan-dian, et al. found an overall relapse rate of5 per 1000 PYR, followed up to a maximumof 15 years (6). The finding in the presentstudy of a relapse rate of 2.7 per 1000 PYR(1.7 per 1000 PYR in regular patients) issignificantly lower than the above,-men-tioned studies. Most likely this is due to thefact that these patients continued dapsonemonotherapy during the observation peri-od. The figure is comparable with that foundfor relapse rates in PB patients after com-pleting MDT (2). Half of the observed re-lapses in this PB group occurred in the first

TABLE 4. Initial classification and clas-sification at time of relapse of paucibacillary(PB) and multibacillary (MB) patients ondapsone monotherapy between 1949 and1976.

Initialclassi-

Classification attime of relapse

fication PB MB Total

PB 15 28 43MB 6 144 150

Total 21 172 193

7 years of observation. At the time of re-lapse, 65% were reclassified as MB.

The average period of observation in theMB group on dapsone monotherapy onlywas 12.4 years (1-22 years). The overallrelapse rate was 10.5 per 1000 PYR (13%of the total group). This overall rate is notsignificantly different (p > 0.05) from thatfound in comparable studies by Kurz, et al.( 5 ) and Cartel, et al. ( 3 ) of MB patients whoalso continued dapsone during the obser-vation period.

The first study, among Indian patients,showed an overall relapse rate of 12.8 per1000 PYR. In the second study, conductedin Polynesia, a relapse rate of 13.9 per 1000PYR was found. The overall relapse rate isalso comparable with the study by Waters,et al. ( 8 ), who described relapses in 362 in-stitutionalized lepromatous patients. Thesepatients had been treated for about 20 yearswith fully supervised dapsone before thedrug was discontinued. They were activelyfollowed up for 8-9 years, and a relapse ratewas found of 10.4 per 1000 PYR. Morerecently Becx-Bleumink reported a relapserate among MB patients of 24.8 per 1000PYR after being released from dapsonemonotherapy on an average of 6.6 years pre-viously ('). The same author reported a re-lapse rate of 2.4 per 1000 PYR for MB pa-tients after completing MDT with an averagefollow up of 4.7 years (2 ).

As with the PB group, only half of therelapses in the present study occurred in thefirst 7 years of observation. The MB patientswho received dapsone together with an al-ternative antileprosy drug had an averagefollow up of 11.9 years. The overall relapserate was 17.9 per 1000 PYR (21% of thetotal group). The difference with the MB

62, 3^Smith and Richardus: Relapse Rates in Pre-MDT Era^357

group of patients who received dapsonemonotherapy only is not significant (p >0.05). From this study it is shown that theinclusion of thiambutosine, thiacetazone,isoniazid or streptomycin for at least 3months in the therapy regimen has not beenof any benefit at all in terms of the relapserate.

In conclusion, it can be noted that thefindings of this study basically confirm theconclusions reached in previous reports asfar as relapse rates expected in PB and MBpatients on dapsone monotherapy. It illus-trates the superiority of the currently usedMDT regimens, both from an operationaland economical point of view. It also em-phasizes the need that all MB patients whohave been treated with dapsone, regardlessthe duration, should receive MDT. How-ever, this study does show that half of therelapses in the PB and MB groups describedoccur after 7 years of follow up. This shouldteach us that, even with MDT, relapses canbe expected after many years, and provisionshould be made for this when planning onpolicies for the follow up of patients releasedfrom treatment after MDT. Since long-termfollow up is not feasible in most programs,patients who have completed MDT shouldbe educated about the need to report backimmediately if any new signs or symptomsof active disease develop. The inclusion ofthiambutosine, thiacetazone, isoniazid and/or streptomycin for at least 3 months intherapy regimens with dapsone in the pre-MDT era did not prevent relapses from oc-curring.

SUMMARYRelapse rates were studied in patients

from northern Thailand who were startedon dapsone monotherapy between 1949 and1976. Included are a group of patients who,for various reasons, also received combi-nations of dapsone and thiambutosine, thi-acetazone, isoniazid and streptomycin. Theoverall relapse rate in paucibacillary pa-tients on dapsone monotherapy only was2.7 per 1000 person-years at risk (PYR) (av-erage observation period 13.9 years). In themultibacillary patients who received dap-sone monotherapy only, the relapse rate was10.5 per 1000 PYR (average observationperiod 12.4 years). In both groups it wasfound that 50% of the relapses occurred af-

ter the seventh year of follow up. The over-all relapse rate in those patients whose treat-ment included thiambutosine, thiacetazone,isoniazid and/or streptomycin for at least 3months was 17.9 per 1000 PYR (averageobservation period 11.9 years). The differ-ence with the multibacillary patients treatedwith dapsone monotherapy only is not sig-nificant. It is concluded that alternative an-tileprosy drugs included in therapy regi-mens with dapsone in the pre-MDT era didnot result in relapses occurring less often.

RESUMENSe estudió la frecuencia de recaidas en pacientes del

none de Tailandia que empezaron su tratamiento demonoterapia con dapsona entre 1949 y 1976. Asi mis-mo se incluyO un grupo de pacientes que, por diversasrazones, también recibieron combinaciones de dap-sona y tiambutosina, tiacetasona, isoniazida y estrep-tomicina. Se encontrO que, en un period() promediode observaciOn de 13.9 afios, la frecuencia general derecaida en los pacientes paucibacilares tratados solocon dapsona fue de 2.7 por 1000 personas-ailos enriesgo (PYR). En los pacientes multibacilares que re-cibieron solo la monoterapia con dapsona la frecuenciade recaida fue de 10.5 por 1000 PYR en un period()promedio de observaciOn de 12.4 atios. En ambos gru-pos se encontrO que 50% de las recaidas ocurrierondespués del séptimo azio de seguimiento. La frecuenciaglobal de recaida en aquellos pacientes tratados ademdscon tiambutosina, tiacetasona, isoniazida y/o estre-promicina, cuando menos durante 3 meses, fue de 17.9por 1000 PYR en un periodo promedio de observaciónde 11.9 afios. La diferencia con los pacientes multi-bacilares tratados solo con dapsona no fue significativa.Se concluyc que las drogas antileprosas alternativasincluidas en el esquema de tratamiento con dapsonaantes de la era de la poliquimioterapia no disminuyOla frecuencia de recaidas.

RÉSUMÉ

Les taux de récidive ont été étudiés chez des maladesdu nord de la Thailande qui avaient commence unemonothérapie a la dapsone entre 1949 et 1976. On ya inclu un groupe de malades qui, pour differentes rai-sons, avaient aussi recu des combinaisons de dapsoneet thiambutozine, thiacetazone, isoniazide et strepto-mycinc. Le taux global de récidive des malades pau-cibacillaires mis sous la seule monothérapie a la dap-sone était de 2,7 pour 1000 personnes-annees a risque(PAR) (periode moyenne d'observation 13,9 ans). Chezles malades multibacillaires sous la seule monotherapiea la dapsone, le taux de recidive emit de 10,5 pour1000 PAR (periode moyenne d'observation 12,4 ans).On a observe dans les deux groupes que 50% des re-cidives survenaient aprés la septiéme armee de suivi.


^Le taux global de recidive chez les malades dont le^3.traitement comprenait de la thiambutosine, du thia-cetazone, de l'isoniazide et/ou de la streptomycine pourun minimum de 3 mois était de 17,9 pour 1000 PAR(periode moyenne d'observation 11,9 ans). La diffe-

^rence avec les malades multibacillaires traits seule-^4.ment par dapsone en monothérapie nest pas signifi-cative. On en conclut que les medicaments anti-léprealternatifs inclus avec la dapsone dans les regimes the-

^rapeutiques qui ont precede l'époque de la PCT n'ont^5.pas result& en une diminution des recidives.

6.

REFERENCES1. BECX-BLEUMINK, M. Relapses in leprosy patients^7.

after release from treatment from dapsone mono-therapy; experiences in the leprosy control programof the All Africa Leprosy and Rehabilitation Train-

^ing Center (ALERT) in Ethiopia. Int. J. Lepr. 60^8.(1992) 161-172.

2. BECX-BLEUMINK, M. Relapses among leprosy pa-tients treated with multidrug therapy: experience inthe leprosy control program of the All Africa Lep-rosy and Rehabilitation Training Center (ALERT)

^

in Ethiopia; practical difficulties with diagnosing re-^9.lapses; operational procedures and criteria for di-agnosing relapses. Int. J. Lepr. 60 (1992) 421-435.

CARTEL, J.-L., BOUTIN, J. P., SPIEGEL, A., PLICHART,R. and Roux, J. F. Longitudinal study on relapsesof leprosy in Polynesian multibacillary patients ondapsone monotherapy between 1946 and 1970. Lepr.Rev. 62 (1991) 186-192.JESUDASAN, K., CHRISTIAN, M. and BRADLEY, D.Relapse rates among nonlepromatous patients re-leased from control. Int. J. Lepr. 52 (1983) 304-310.KURZ, X. M., DECLERQ, E. E. and VELLUT, C. M.Rate and time distribution of relapses in multiba-cillary leprosy. Int. J. Lepr. 57 (1989) 599-606.PANDIAN, T. D., MULIYIL, J. and VELLUT, C. Riskof relapse among non-lepromatous patients releasedfrom treatment after dapsone monotherapy. Lepr.Rev. 62 (1991) 288-296.RICHARDUS, J. H. and SMITH, T. C. Increased in-cidence of hypersensitivity reactions to dapsone af-ter introduction of multidrug therapy. Lepr. Rev.60 (1989) 267-273.WATERS, M. F. R., REES, F. J. W., LAING, A. B. G.,KHOO KAH FAH, MEADE, T. W., PARIKSHAK, N. andNORTH, W. R. S. The rate of relapse in lepromatousleprosy following completion of twenty years of su-pervised sulphone therapy. Lepr. Rev. 57 (1986)101-109.WHO STUDY GROUP. Chemotherapy of leprosy forcontrol programmes. Geneva: World Health Or-ganization, 1982. Tech. Rep. Ser. 675.

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