INTERNATIONAL. JOURNAL OF LEPROSY^ Volume 65, Number 2Printed in the U.S.A.

(ISSN Ol-48-916X)

Risk of Relapse in Leprosy After Fixed-DurationMultidrug Therapy'

Huan-Ying Li, Lu-Fang Hu, Wan-Biao Huang, Guo-Cai Liu, Lian-Chao Yuan,Zheng Jin, Xiong Li, Jin-Lan Li, and Zhong-Min Yang?

Multidrug therapy (MDT) has been im-plemented world wide since its introductionin 1982 ( 10) and the relapse rate has beenvery low ( 8). However, few publications re-fer specifically to relapse rates after fixedduration MDT (FD-MDT) ("). In a fieldstudy in 1983 involving two independentteams on the therapeutic effect of MDT,ending the regimen at 24-27 months formultibacillary (MB) and 6-10 months forpaucibacillary (PB) leprosy, it was notedthat the clinical symptoms, bacterial index(BI) and specific infiltration continue to re-solve after therapy ( 5). Encouraged withthese preliminary results, and with the aimto enhance the progress of leprosy control,a control program with FD-MDT waslaunched in 1986 in the most prevalent andthe most difficult areas for leprosy controlin the country. The present paper presentsthe findings on the risk of relapse for lep-rosy patients who have completed FD-MDT within the specified period and havebeen surveyed annually from 1 to 9 yearsafter therapy.

MATERIALS AND METHODSThe areas chosen for leprosy control with

FD-MDT involved 59 counties from seven

' Received for publication on 8 October 1996.Accepted for publication in revised form on 11February 1997.

= H. Y. Li, M.D., M.P.H., Senior Researcher; L.C.Yuan, Programmer, Beijing Tropical Medical ResearchInstitute, 95 Yong An Lu, Beijing 100050, China. L.F.Hu, M.D., Director; Z. Jin, Statistician, SichuanProvincial Institute of Dermatology, Changdu, SichuanProvince 610031, China. W. B. Huang, M.D., Direc-tor; X. Li, Statistician, Yunnan Provincial Institute ofDermatology, Kunming 650223, China. G.C. Liu,M.D., Director; J.L. Li, Statistician, Guizhou Provin-cial Institute of Dermatology, Guiyang 550001, China.Z.M. Yang, M.D., Research Member, Institute of Can-cer, Chinese Academy of Medical Sciences, Beijing100021, China.

prefectures of the three southwesternprovinces of China, covering 178,758 sq.km , a population of 19 million (1986) andabout 10,000 leprosy patients of whom72% are multibacillary (1986-1995). Theseprefectures are composed of very ruggedmountainous terrain, are populated by morethan 20 different ethnic groups, and havethe highest leprosy prevalency in the coun-try (0.34-0.74/1000/county, 1985) (TheFigure).

For the present study, a 10-day trainingcourse on leprosy control with FD-MDTwas held in Xichang, the capital of Liang-shan Yi Autonomous Prefecture in Novem-ber 1985 for 10-12 leprosy workers (LW)from the provincial, prefectural and countylevels per province. During this course,methods in case finding, diagnosis (clinical,smear, biopsy), treatment with FD-MDT(MB 24 monthly doses, PB 6 monthlydoses of MDT), regularity (MB within 36and PB within 9 months), management ofleprosy/drug reactions, annual clinical andbacteriological surveillance, as well as arecording and reporting system were dis-cussed and standardized. Based upon theselectures and the accompanied practicals, amanual was prepared and distributed to allLW from the 59 county leprosy control sta-tions (SDCS). All patients who did notcomplete FD-MDT in the specified periodof time are excluded from the present study.

For the prescription of FD-MDT, the pa-tients were designated as PB ( 1 "), but in order to study relapses, all patients were clas-sified by the Ridley and Jopling scale clini-cally and histopathologically.

All new patients. suspected relapses andsevere leprosy/drug reactions were first ex-amined by the responsible county LW,checked clinically, bacteriologically andhistopathologically, if necessary, by the cor-responding specialist from the Provincial

238

30°T I B E IT

I C.4^H^I

S I^H U A N

Chengdu

S H^A N-

X IH U -

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U -

A N

26°

(YUNNAN

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C U A N C X

Cancer

1 0°98° 106°

Lzaie^1 : 1,50,00c

100 2C0 500 400 km

65,2^ Li, et al.: Relapse After FD-MDT^ 239

THE FIGURE. Map of Yunnan, Guizhou and Sichuan Provinces, China, showing FD-MDT prefectures.

Institute of Dermatology (PIOD), usuallywithin 2-3 weeks, and the necessary regi-men and/or treatment prescribed. Con-firmed relapses were required to complete aspecial form with all the relevant data be-fore, during and at the end of FD-MDT,plus data at each annual surveillance by theleprologist from PIOD.

Criteria of regularityThe monthly supervised dose was to be

taken within 5 days of the scheduled dateand the daily self-administered dose was tobe taken for at least 20 days per month. Theentire course should be completed within36 months for MB and 9 months for PB.

Criteria of relapseMB. Criteria for a relapse in MB pa-

tients included: a) Insidious appearance ofnew lesions, enlargement of old lesions, atleast 6 months after completing a regularcourse of FD-MDT; b) an increase in acid-fast bacilli (AFB) of ^2+ from the samesite of the previous examination; c) specificinfiltration plus postive AFB in thehistopathology of the suspected lesion.

PB. Criteria for a relapse in PB patientswas the same as for MB except for AFB.

A 5-day surveillance workshop on cohortanalysis was conducted 10 years after theFD-MDT workshop in the prefectural capi-

240^ International Journal of Leprosy^ 1997

TABLI ,. 1. Relapse rates in MI3 and PI3 leprosy by chemotherapy before fixed-durationMDT (ED-1141Y1) in seven prefectures of Yunnan, Gui:hou, Sichuan Provinces, ChinaI9S6-1995.

Province Counties/Prefectures.'

Without previous chemotherapy With previous chemotherapy 'to tal

No. pts/py. Relapse 1/1000 No. pts/py. Relapse 1/1000 No. pts/py.

MBYunnan 23/3 S 15/2,598 0 0.00 957/4,962 2 0.40Guizhou 16/2 695/2,059 (1 0.00 1,336/7,157 I 0.14Sichuan 20/2 808/2,486 0 0.00 1,370/7,542 2 0.27Sub-total 59/7 2,3 1 S/7,I43 0 0.00 3,663/19,661 5 0.25 5,981/26,804 pyMean 3.1^yrs. 5.36 yrs. 4.5 yrs.

P13Yunnan 23/3 497/1,7(14 2 1.17 229/899 3 3.34Guizhou 16/2 163/481 0 0.00 508/2,208 0 0.00Sichuan 20/2 218/856 0 0.00 711/2,964 0 0.00Sub-total 59/7 878/3,041 2 0.66 1,448/6,071 3 0.49 2,326/9, 112 pyMean 3.5 yrs. 4.2 yrs. 3.9 yrs.

MB + PB 59/7 3,196/10,184 2 0.20 5,111/25,732 8 0.27 8,307/35,916 py

Number of counties/number of prefectures.

tal of Bijie, Guizhou Province (October26-30, 1994) for 10 LW responsible for thestatistics from the three levels of leprosyadministration of each province. This work-shop concentrated on the construction of acohort analysis !Orin, and practicals for theLW on 30 history records of patients whohave completed FD-MDT from Qian-XiCounty of Bijie Prefecture.

For the present study, each county lep-rosy team was required to complete this co-hort form for all patients who were on FD-MDT in the county. Data were entered intothe databank and analyzed in Beijing.

RESULTSBetween 1983 and 1995, 10,047 leprosy

patients were put on FD-MDT. Excluding417 deaths (MB 352, PB 65; 4.2%), 303lost/moved out (MB 262, PB 41; 3.0%), 74irregularity (MB 62, PB 12; 0.7%) duringFD-MDT and 946 patients still on FD-MDT by the end of 1995, all together 8307(MB 5981, PB 2326) patients meet the cri-teria for the present study. Among them,3196 had never received any antileprosytherapy and 5111 had had some months/years of dapsone or dapsone plus rifampinbefore FD-MDT (Table 1).

Risk of relapseA total of 5981 MB patients had a regular

course of FD-MDT, 110 of whom havebeen followed for 9 years and 6 for 10

years. Since the implementation of FD-MDT in 1986, new patients detected andcompleting FD-MDT were added to the co-hort each year. The period of surveillancetherefore varies; with the exemption of ir-regularity (62), deaths (358) and lost (182),the total follow-up period is 26,804 person-years (py). Five MB relapses (0/7143 pywithout previous chemotherapy; 5/19,661py with previous chemotherapy) were de-tected. These live MB relapses occurredduring the fourth (1), fifth (2) and seventh(2) year of surveillance, giving a mean re-lapse rate of 0.19/1000 py and a cumulativeprobability of relapse of 2.88/1000 in theseventh year of surveillance (Table 2).

All together 2326 PB patients had com-pleted a regular course of FD-MDT and1783 PB patients have completed 5 years ofsurveillance. Five relapses occurred, 4 dur-ing year 4 and another during year 5 of fol-low up, giving a mean relapse rate of0.55/1000 py excluding death (132) andlost (138). The cumulative probability ofrelapse is 3.29/1000 in year 5 of surveil-lance (Table 3).

Six PB patients relapsed after year 5 ofthe surveillance period (3 during year 7, 2during year 8 and 1 in year 9 after FD-MDT) (Table 4). These relapses were notincluded in the relapse rates; they were self-reported cases and the surveillance periodhad terminated at the end of 5 years of fol-low up.

Yrs.follow

up

No.PB

to hefollowed

No.PB

followed< 1 & n yrs.

Lost^Died RelapsedWithdrawals

PYCumulative

Relapse/^probability of1000 py^relapse durine,

yr./ I 000S.D.

65, 2^ Li, et al.: Relapse After FD-MDT^ 241

TABLE 2. Risk of relapse in 5981 MB patients after FD-MDT seven prefectures ofYunnan, Guizhou and Sichuan Provinces, China (1985-1995)."

Yrs.follow

u P

No.MBto he

followed

No.MB

followed< I & n yrs.

WithdrawalsPY

Relapse/1000 py

Cumulativeprobability ofrelapse during

yr./1 000

S.D.Lost Died Relapsed

1 5,981 431 50 80 0 5,700.5 0.00 0.00 0.005,420 378 43 82 0 5,168.5 0.00 0.00 0.00

3 4,917 426 30 47 0 4,665.5 0.00 0.00 0.004 4,414 391 27 54 I 4,178.0 0.24 0.24 0.005 3,941 813 18 40 2 3,505.5 0.57 0.81 0.246 3,068 1,351 10 36 0 2,369.5 0.00 0.81 0.477 1,671 1,390 4 11 _2 968.5 2.07 2.88 0.478 264 148 0 6 0 187.0 0.00 2.88 1.549 110 102 0 2 0 58.0 0.00 2.88 1.5410 6 6 0 0 0 3.0 0.00 2.88 1.54Total 181 358 5 16,804.0 0.19

Mean relapse rate: 5/26,804 = 0.19/1000 person-years.

Of the total 11 PB relapses, 7 were origi-nally diagnosed as BT and 4 as TT leprosy(Table 5). Eight PB patients relapsed intoMB and 6 of them had ^5 lesions and/or ^3nerve involvements at the start of therapy.In the 7 BT relapses, 2 BT (Patients 1 and2, Table 4) were clinically diagnosed ashaving a reversal reaction at year 4, and IBT patient with a reaction (Patient 6, Table4) was a self-reported case in year 7 afterFD-MDT. All three remained BT inhistopathology. A late reversal reaction islikely to be an indication of relapse, and thetwo BT patients with reversal reaction atyear 4 of surveillance were, therefore,counted as relapses.

DISCUSSIONThe annual surveillance of the present

study follows the rules set forth at theFourth National Leprosy Conference (Nan-chang 1990): MB for 10 years and PB for 5

years after MDT, which is longer than theperiod required by WHO ( 7 ). Using the life-table method, the mean relapse by person-years of observation for each year after FD-MDT and the cumulative probability of re-lapse for the successive years of observationare calculated. The latter not only providesthe probability of relapse for an individualpatient at any year after FD-MDT, but alsohas the advantage of comparing the thera-peutic effect with other treatment regimensat different time intervals.

In 3663 MB patients who had receivedsome chemotherapy prior to FD-MDT, 5 re-lapses occurred: I in year 4 and 2 each dur-ing years 5 and 7 of follow up, giving amean relapse rate of 0.25/1000 py. Togetherwith the zero relapse in 2318 NIB patientswithout pevious chemotherapy and 7143 pyof follow up, the mean relapse rate is 0.19/1000 py (Table 2). This rate is much lowerthan the world-wide figure of 0.84/1000 py

TABLE 3. Risk of relapse in 2326 PB patients after FD-MDT in seven prefectures ofYunnan, Guizhou and Sichuan Provinces, China (1984-1995)."

1 2326 66 26 29 0 2265.5 0.00 0.00 0.002 2205 81 34 33 0 2131.0 0.00 0.00 0.003 2057 66 56 34 0 1979.0 0.00 0.00 0.004 1901 67 18 29 4 1844.0 2.17 2.17 0.005 1783 1771 4 7 1 892.0 1.12 3.29 1.08Total 138 132 5 9111.5 0.19

Mean relapse rate: 5/9111.5 = 0.55/1001) person-years.

International Journal of Leprosy^ 1997

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65, 2^ Li, et al.: Relapse After FD-MDT^ 243

TABLE 5. Change in type of relapsesafter FD-MDT.

Type of leprosy at relapseBeforeMDT MB PB Total

LL BL BB BT^T

MB^LL 3 I 4BL 1 IBB

PB^BT 3 I 3 7TT 2 2 4

Total 4 6 3 3 16

and is comparable to the relapse rate of0.27/1000 py from India (Table 6).

Elsewhere China (11 counties inYangzhou Prefecture, Jiangsu Province), norelapses were noted after treating 347 MBpatients until smear negativity, 247 ofwhom had 470 py of surveillance after ther-apy ('). Compared with the five relapses in8307 MB patients in the present study(5/26,804 py = 0.19/1000 py), there is nostatistical difference in the relapse rates be-tween MB patients who were treated untilsmear negativity or who had received only24 months of MDT, regardless of slit-skinsmear results at the time of terminatingMDT (x 2 = 0.20, p = 1.00).

The difference in relapse rates betweenMB patients with (5/19,661 py) or without(0/7143 py) chemotherapy before FD-MDTin the present study is also not significant(x 2 = 1.74, p = 0.16, Table 1). Prolongeddapsone monotherapy was widely used in

China before the introduction of MDT, andprimary dapsone resistance was as high as44% ('). Four out of the five MB relapseswere successfully retreated with the MBregimen of FD-MDT (the other pending re-sults of a mouse foot pad study), indicatingthat MDT can overcome the occurrence ofdapsone resistance and its spread.

The mean relapse rate for 878 PB pa-tients without and 1448 PB patients withprevious chemotherapy is 0.55/1000 py,which is also lower than the world-wide fig-ure of 0.96/1000 py and figures fromMalawi (6.0/1000 py) and Indonesia(1.2/1000 py) (Table 6). There is also nostatistical difference between the relapserates of PB patients with (3/6071 py) orwithout (2/3041 py) previous chemotherapyin the present study (x 2 = 0.13, p = 1.00).

According to WHO statistics, 50% ofMB relapses occur within 3 years afterMDT and 75% within 6 years; in PB, 50%of the relapses occur within 21/2 years and75% within 5 years after MDT ( 5 ).

In the present study, no MB patient re-lapse occurred within 3 years and all five ofthe MB relapses occurred 4-7 years afterFD-MDT. In PB patients, 4 relapsed in year4 and I relapsed during year 5 of surveil-lance. There were also 6 late PB relapses, 5relapsed into MB and 1 cannot be differen-tiated from reversal reaction.

It is known that a relapse in a PB patientcan be difficult to distinguish from a rever-sal reaction ( 7). With the recurrence of le-sions plus a histopathological picture of BTleprosy and without any evidence for the

TABLE 6. Relapse rates in MB and PB leprosy after treatment with MDT until smearnegativity and after .fixed-duration MDT from different studies.

Leprosytype County No.MDT patients

Yrs.follow up Relapsep py Relapse/

1000 py

NlultibacillaryWHO(") Multi-center

studyUntil 131(—)/24 mos.

20,141 9 67 79,369 0.84

India(") Polambakkam and Until BI(—) 1,748 9-10 4 15,000 0.27Karigiri

China('') Yangzhou Until BI(—) 257 2— 0 470 0.00Prefecture 24 mos. 5,981 9-10 5 26,804 0.19

Present study

PaucibacillaryWHO(s) Multi-center study 6 mos.^51,553 9 306 319,381 0.96

Malawi(') 6 mos. 484 4 12 1,000 6.00Indonesia(K) 6 mos. 471 5 3 2,500 1.20

Present study 6 mos. 2,326 5 5 9,111 0.55

244^ international Journal of Leprosy^ 1997

presence of AFB, three patients (PB pa-tients 1, 2 and 6, Table 5) were counted asPB relapses. From experiences with MBleprosy, reversal reactions occur more oftenduring the first year of FD-MDT and in thefirst 6 months after FD-MDT, and fall offgradually within 4 years. The BI normallydecreases at the rate of about 0.7/year, gen-erally reaching 0 within 5 years after FD-MDT ( 4). Therefore, it may he assumed thata late reversal reaction is indeed an indica-tion of relapse in PB leprosy. All patientswith lepra reactions after FD-MDT, if re-ceiving prednisone, were simultaneouslytreated with MDT, thus avoiding the lower-ing of immunity and favoring the multipli-cation of AFB during corticosteriod ther-apy. The higher relapse rate in PB patientsis mainly due to misclassification and theprescription of the wrong regimen.

Because of the very difficult field condi-tions, no attempt in differentiation with aI -month trial therapy with prednisone wasmade. All PB relapses were retreated withthe MB regimen of FD-MDT.

All five MB relapses were diagnosed asMB before FD-MDT. Of the 11 PB re-lapses, 8 relapsed into MB and 3 remainedPB which cannot be differentiated from re-versal reaction. Another three PB relapseswere originally AFB positive (PB patients6, 7 and 10, Table 5) and most PB relapseshad ^4 lesions and/or ^3 nerve involve-ments before MDT. Moreover, half of therelapses (7/15) were originally diagnosed asBT leprosy, and the PB MDT regimen wasadministered.

Of the 62 MB patients known to be irreg-ular and excluded from the present study,four relapses/deteriorations (6.5%) wererecorded between years 4 and 7 after theirscheduled date for FD-MDT. Indeed,poorly implemented MDT is better than noMDT (Yuasa, Y. MDT for all: target ori-ented leprosy control programme in the1990s. Paper presented at WHO Consulta-tion on Technical and Operational Aspectsof Multidrug Therapy, Male, Maldives11-15 June 1990).

Based upon the very low irregularity rate(MB: 62/6043 = 1.03%, PB: 12/2338 =0.51%) and the few late relapses, it may beconcluded the FD-MDT is adequate bothfor MB and PB leprosy, provided that thecorrect regimen is prescribed and strict reg-

ularity of drug intake is adhered to. A cor-rect classification at first diagnosis is of ut-most importance. In case of doubt, the MBregimen should be prescribed.

The mean duration of surveillance is only4.5 years for MB leprosy 3.9 years for PB,and for the sake of further reference, we in-tend to follow these groups of patients asset at the Nanchang National Leprosy Con-ference: MB for at least 10 years and PB forat least 5 years after FD-MDT.

As already recommended by WHO, itshould be stressed that there is no need tohave long-term post-MDT surveillance (s),and there is also no need for any bacterio-logical surveillance after a regular course ofFD-MDT. The BI falls at its own course af-ter adequate therapy regardless of the drugregimen. It is known that MB leprosy mayrelapse even 20 years after dapsone therapy( 5 ) and 10 years or more after dapsone plusrifampin therapy ( 2 ). Patients should be re-minded to seek medical care for any recur-rence of symptoms, especially during thefirst year after FD-MDT for leprosy reac-tions and even years after MDT for possiblerelapses. The time and manpower thussaved could be devoted to health education,active case finding, disability prevention,integration of leprosy control into the pri-mary health system and health care, in gen-eral, at the grassroot level.

SUMMARYBetween 1986 and 1995, 8307 leprosy pa-

tients have completed fixed-duration multi-drug therapy (FD-MDT) and were followedannually for possible relapse. The mean re-lapse rate for multibacillary (MB) leprosy is0.15/1000 person-years (py) and for pau-cibacillary (PB) 0.55/1000 py. There is nodifference in the relapse rates between pa-tients with or without chemotherapy beforeFD-MDT. In MB patients, the five relapsesoccurred between 4 and 7 years; in PB pa-tients, five relapses occurred at 4-5 yearsafter FD-MDT. Six additional PB relapsesself-reported 1-4 years after the 5-year sur-veillance period and were not included inthe relapse rates. Most PB patients relapsedinto MB due to wrong classification and in-sufficient therapy. For the known 62 irregu-lar MB patients the cumulative relapse rateis 6.5%.

65, 2^ Li, et al.: Relapse After FD-MDT^ 245

RESUMENEntre 1986 y 1995, 8307 pacientes con Iepra habian

completado su tratamiento con poliquimioterapia deduraciOn fija (PQT y estaban bajo supervisiOn an-ual para detectar posibles recaldas. La tasa promediode recalda pant los pacientes multibacilares (MB) tuede 0.15/1000 persona-aims (pa) y para los pauci-hacilares (PB), de 0.55/1000 pa. No hubieron dife-rencias en las tasas de recalda entre los pacientes con osin quimioterapia antes de Ia PQT DF. En los pacientesMB, las 5 recaldas ocurrieron entre los anos 4 y 7; enlos pacientes PB, ocurrieron 5 recaldas entre los anos 4y 5 despues de Ia PQT DF. No se incluyeron en astasas de recaida, seis recaldas PB adicionales autore-portadas, ocurridas entre I y 4 afios despues del peri-od() de seguimiento de 5 anos. La mayoria de los pa-cientes PB recayeron como MB debido a una clasiti-caci6n erronea y a la terapia insuticiente. Para los 62pacientes MB conocidos coin() irregulares, Ia tasa acu-mulativa de reed& fire del 6.5%.

RÉSUMÉ

Entre 1986 et 1995, 8307 malades de Ia lepre onttermitig one polychimiotherapie de duree lixe (PCTDF) et ont ete suivis chaque annee pour des rechuteseventuelles. Le taux moyen de rechute pour Ia lepremultibacillaire (MB) est de 0.15/1000 personnel-an-flees et pour Ia lepre paucibacillaire de 0.55/1000 per-sonnes-annees. II n'y a pas de diUrence dans les tauxde rechute entre les patients qui avaient suivi ou nonone chimiotherapie avant Ia PCT DF. Chez les maladesMB, les 5 rechutes soot survenues entre 4 et 7 ans;chez les patients PB, chic] rechutes soot surevnues 4-5ans apres la PCT DF. Six rechutes PB supplementairesont ere rapportees par les patients eux-memes 1 a 4 ailsapres Ia periode de surveillance de 5 ans, et n'ont pasere inclues dans les taux de rechutes. La plupart despatients PB rechutaient sous one forme MB, suite aune mauvaise classification et It un traitementisant. Pour les 62 patients MB irreguliers count's, letaux cumule de rechute est de 6.5%.

Acknowledgment. This investigation receivedtechnical and financial support from the UNDP/World

Bank/WHO Special Programme for Research andTraining in Tropical Diseases (TDR).

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