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JOURNAL OF LEPROSYAnd Other Mycobacterial Diseases

VOLUME 60, NUMBER 4^ DECEMBER 1992

Relapses in Multibacillary Leprosy Patients AfterStopping Treatment with Rifampin-containing

Combined Regimens'Marchoux Chemotherapy Study Group 2

(prepared by Pierre Jamet and Baohong Ji)

Until multidrug therapy (MDT) was rec-ommended by a WHO Study Group in 1981( 20), dapsone (DDS) administration asmonotherapy, often of life-long duration,was the standard treatment of individualleprosy patients, and the standard regimenfor leprosy control programs throughout theworld. A large proportion of patients withmultibacillary (MB) leprosy sustained re-lapse during DDS monotherapy ( I, 10, I3. 1)),

many of whom demonstrated Mycobacte-rium leprae resistant to DDS ( 7). Becausethe relapse rate among patients whose treat-ment was stopped after 20 years of dailysupervised treatment with DDS was foundto be 1 per 100 patient-years of observationel, it appeared that ensuring the regularityof DDS monotherapy over the long termdid not substantially change the picture.Therefore, it was clear that attempts to con-

' Received for publication on 5 May 1992; acceptedfor publication on 11 June 1992.

2 Members of the Study Group are: Leopold Blanc,Pierre Bobin, Denis Daumerie, Guy Discamps, JacquesGrosset, Gerard Grossetete, Jean Alain Husser, PierreJamet, Baohong Ji, Max Nebout, Steffan Pattyn, andIssa Traore.

Reprint requests to: Dr. Jacques Grosset, Bactériol-ogle et Virologie, Faculte de Médecine Pitie-Salpe-triere, 91 Blvd. de l'Hôpital, 75634 Paris 13, France.

trol leprosy by DDS monotherapy were fail-ing, and that it was necessary to replace thistreatment by the administration of a com-bination of drugs, a method that had provedsuccessful in preventing the relapse of tu-berculosis and the selection of drug-resis-tant mutants of M. tuberculosis ("). How-ever, unless the combined treatment waseffective if administered for only a limitedperiod of time, and led to a more rapid"cure," it would be unlikely to increase theeffectiveness of leprosy control activities.

Because the very powerful and rapid bac-tericidal activity of rifampin (RMP) againstM. leprae had been demonstrated in earlierstudies ( 2 . IS), various short-term RMP-con-taining combined regimens were testedamong MB patients at the Institut Mar-choux, Bamako, Mali, during the decade be-ginning in the mid-1970s. Despite manydifficulties, a majority of the patients werefollowed up after stopping treatment, pro-viding a unique opportunity to assess theeffectiveness of different RMP-containingcombined regimens in terms of relapse rates.A great majority of the relapses describedin the present communication have beenconfirmed by mouse foot pad inoculation,a method rarely employed in studies of re-lapse of MB leprosy ( 3 ' 5 . '").

525

526^ International Journal of Leprosy^ 1992

MATERIALS AND METHODS

Regimens. Between 1977 and 1986, 12RMP-containing combined regimens, asshown in Table 1, were tested. The totalduration of treatment ranged from 1 to 24months, and the duration of RMP admin-istration ranged from a single dose to dailydoses for 24 months. The administration ofall the drugs, even those administered daily,was supervised. No subsequent antileprosytherapy was prescribed to patients after thetrials.

Patients. A total of 532 MB patients wererecruited into the trials. All of them dem-onstrated active leprosy skin lesions with abacterial index (B1) of 2+ and a negativeMitsucla lepromin reaction ( < 3 mm in di-ameter). Histopathological examination hadbeen conducted in 382 (72%) patients, andthe classification of lepromatous (LL) orborderline lepromatous (BL) leprosy hadbeen confirmed. The patients were hospi-talized during the trials until completion ofchemotherapy. All patients treated with reg-imens A, B, A2, E2, C, and S6 had not beentreated previously. In patients treated withother regimens, 55.9% (214/383) had notbeen treated previously, 37.1% (142/383)had been treated with various durations ofDDS monotherapy, and 7.0% (27/383) hadbeen treated with various RMP-containingregimens, mostly single-dose RMP 1500 mgplus daily DDS. Regimens REC and RPCwere administered to patients who had beentreated previously with DDS monotherapyfor longer than 5 years, or who had relapsedwith DDS-resistant M. leprae proven bymouse foot pad inoculation.

Of the 532 patients, 437 completed thescheduled treatments. Among the latter, 53are not suitable for analysis of relapse: 11had never returned for follow-up exami-nation by the end of May 1991; and 42 hadbeen seen only during the first 12 monthsafter completing treatment (Table 4). Thus,among the 437 eligible patients, only 384cases have been seen at least once later than12 months after completing treatment, andmay be used for calculating the relapse rate(Table 4). Of these 384 cases, 255 cases hadnot received antileprosy treatment previ-ously, 46 cases had been given DDS mono-therapy for less than 5 years, 22 with single-dose RMP 1500 mg plus daily DDS, 61 with

DDS monotherapy for at least 5 years, and12 of the latter group had relapsed withproven DDS-resistant Al. leprae.

Procedures of follow up. At the time ofeach patient's visit after treatment had beencompleted, a thorough clinical examinationwas carried out with special emphasis onthe evolution of preexisting leprosy lesionsand detection of suspected new lesions; skinsmears were taken from the six sites origi-nally examined, and from any suspected newlesion(s); and a urine specimen was collect-ed for DDS analysis. The slides of the skinsmears were stored in the dark, at least untilthe results of the next examination becameavailable.

Criteria of relapse. Relapse was sus-pected when the BI at any site was foundto have increased by at least 2+ over theprevious value and the BI increase was con-firmed by reexamination; or when a definitenew lesion was observed with a BI greaterthan that in any preexisting lesion. In mostcases, a skin biopsy was taken from the sus-pected new lesion for enumeration of AI.leprae, expressed as the log,„ number pergram of tissue (LOGAFB), mouse foot padinoculation to test the viability ('') and drugsusceptibility ( 8) (mainly to RMP and DDS)of the organisms, and histopathological ex-amination. The first two items were ex-amined mainly at the Institut Marchoux;some of the specimens were examined inthe laboratory of S. R. Pattyn (Antwerp) orof J. Grosset (Paris). Detection of viableorganisms, defined as multiplication to10 5 organisms per foot pad after inoculationof 5 x 10 3 organisms per foot pad of im-munocompetent mice, was taken as confir-mation of the relapse. The histopathologicalexaminations were carried out in the labo-ratory of S. R. Pattyn or that of G. Discamps(Bordeaux). Histopathological relapse wasdefined as the appearance of young histio-cytic granulomas containing solidly stainedbacilli either isolated or in globi.

Statistical analysis. The relapse ratesamong groups of patients treated with var-ious regimens were compared by Fisher'sexact probability test. The "incubation pe-riod" of relapse after completion of treat-ment was calculated as the number ofmonths between stopping treatment and theappearance of the relapse, and the latter wasdefined as the midpoint between the dates

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TABLE 2. LiNt of )4 relapses confirmed hy mouse .1O01 pad inoculation.

Regimen Caseno.

Completedtreatme nt

Lowest IIIduring

follow up

Relapse

DateInca-

batton"(nun.)

01' LOGAFB MEP'Date III" Date^111'

R EC 13 1/81 5 1 2/87^14 3/88 79 5+ 10" 3/3RE(' 3 2/81 5+ 2/88^0 11/89 89 5+ 10" 2/10RED 5 7/81 0 Defaulted until 10/85 18 5+ 10" 7/7

relapseRED 6 7/8I 5+ 4/85^1+ 11/85 48 5+ 10" 3/3RED II 8/81 5+ 1/86^3+ 6/86 56 6+ 101" 6/6RED 13 3/81 4+ 4/86^2+ 11/89 79 5+ 10" 2/10A 16 5/78 3+ 2/84^2+ 4/85 76 5+ ND 1/7A 15 6/78 3+ 2/86^0 6/87 100 4+ 10" 3/7A 18 6/78 5+ 2/83^2+ 7/88 89 5+ 10" 5/7A 6 5/78 5+ 6/83^2+ 4/89 101 5+ 10" 2/6A 14 6/78 5+ 6/83^3+ 12/90 104 5+ 10' 6/1013 10 10/78 2+ 6/83^3+ 4/85 74 5+ 10" 5/513 II 2/79 4+ 10/85^0 10/87 85 4+ 10" 4/6It 2 9/78 3+ 1/88^1+ 12/89 120 5+ 10" 6/10C 44 3/83 4+ 11/85^2+ 11/87 26 5+ 10" 5/9C 73 8/85 5+ Defaulted until 9/86 27 5+ 10" 11/15

relapseC 7 12/81 4+ 10/85^4+ 8/86 48 5+ 10" 12/15C 38 3/83 4+ 2/88^1+ 6/89 65 5+ 10" 4/5C 61 4/84 3+ 4/89^2+ 4/90 65 6+ 10" 5/10C 16 10/81 4+ 6/89^1+ 2/90 94 5+ 10" 7/8E2 99 11/85 4+ 2/88^4+ 10/88 35 5+ 10'" 6/6E2 63 4/84 4+ 6/86^3+ 3/88 30 5+ 10" 6/6E2 51 10/83 4+ 1/89^0 7/90 72 4+ 10' 4/6WI10/MDT 196 6/87 3+ 3/89^1+ 4/90 27 5+ 10" 5/10RPC I 1/82 6+ 10/87^3+ 8/89 80 5+ 10'" 5/6RPD 251 11/85 5+ 2/88^4+ 11/88 24 5+ 10'" 3/51Z BD 66 5/84 5+ 7/85^5+ 6/88 31 5+ 10'" 3/7It BD 128 12/84 5+ 4/87^3+ 7/88 37 5+ 10' 6/6RPD 6 10/84 5+ 12/86^5+ 2/89 44 5+ 10' 6/6R I'D 3 1/82 5+ 9/85^2+ 3/86 47 3+ 10" 5/5RPD 174 5/85 5+ 3/89^1+ 2/90 52 5+ 10' 4/10RPD 36 10/81 5+ 5/86^2+ 12/88 59 5+ 10" 6/6RPD 4 11/81 5+ 2/88^0 4/89 78 5+ 10" 4/6RFD 33 7/82 5+ 1/88^1+ 8/90 90 5+ 10'" 2/8S4 51 4/86 3+ 4/88^4+ 6/90 36 6+ 10' 4/8S4 56 3/85 5+ s2/87^5+ 10/89 23 6+ 10'" 4/6S4 43 10/84 5+ 12/86^3+ 3/87 27 5+ 10" 6/6S4 254 10/85 5+ 2/87^2+ 2/89 28 6+ 101" 6/6S4 50 2/85 4+ 2/87^5+ 3/88 29 5+ 10" 1/7S4 137 11/84 5+ Defaulted until 1/90 31 6+ 101" 1/6

relapseS4 231 7/85 5+ 7/87^5+ 6/88 32 5+ 10" 4/4S4 67 2/84 5+ 2/87^4+ 8/87 36 5+ 10' 8/1 IS4 80 4/84 5+ 5/88^2+ 11/89 45 6+ 10"' 4/10S4 267 12/85 4+ 1/89^3+ 7/90 45 5+ 10" 4/6S4 159 12/84 6+ 12/89^3+ 1/90 54 4+ 10' 2/10S4 3 1/84 Unknown as part 3/90 61 5+ 10" 8/10

of the file lostS4 1 5/84 5+ 3/89^2+ 1/90 64 5+ 10" 2/6S4 70 3/84 6+ 2/89^5+ 2/90 64 6+ 10' 2/8S4 275 2/86 1+ 6/88^0 5/90 40 4+ 10' 5/7S4 10 2/84 5+ 1/90^2+ 5/90 71 5+ 10' 4/6S4 27 1/84 4+ Defaulted 7/90 54 5+ 10" 4/7S4 202 4/85 5+ 4/90^1+ 10/90 63 5+ 10" 8/8S4 9 2/84 5+ 4/90^3+ 10/90 77 5+ 10" 8/8S6 10 3/83 4+ 10/86^4+ 10/89 61 5+ 10' 4/10

Maximum score of skin smears taken from 6 sites." Refers to the incubation period of appearance of relapse from stopping chemotherapy. Date of relapse defined

as the midpoint between date of last examination without relapse and the first examination with evidence ofrelapse.

Results of mouse foot pad inoculation: no. of mice showing multiplication of M. leprae/no. of mice harvested.

60, 4^Marehoux Chemotherapy Study Group: MB Relapses^529

TABLE 3. List qf suspected re/apses either nonconfirmed or pending results or not doneby mouse foot pad inoculation.

Regi-men

Caseno.

Completedtreatment

Lowest 131 duringfollow up

Suspected relapse

DateIncu-

bation"^134'( n10.)

LOGAFB

M FP'Date Ill' Date^131'

RFC 8 2/81 3+ 2/87^0 3/89 86 5+ RP" 0/7A2 II 12/81 5+ 1/86^2+ 4/89 75 5+ 10' 0/8RPC 23 6/82 5+ 2/89^3+ 11/89 36 5+ 10' 0/10S4 53 2/85 4+ Defaulted 4/90 27 5+ 10' 0/10S4 248 11/85 5+ Always 5+ 5/89 38 5+ 10" 0/8C 54 11/83 5+ Defaulted 9/90 53 5+ 10"' 0/10It PD 7 3/82 5+ 2/87^0 7/90 70 5+ 107 0/10RPD 81 6/84 5+ 10/89^3+ 5/91 75 5+ ND" NDS4 190 1/85 5+ 3/89^4+ 10/89 40 5+ 10' NDRPD 237 3/86 5+ 11/89^2+ 11/90 53 4+ ND P"II 17 1/79 5+ Defaulted 2/91 76 5+ 10" PS4 233 12/85 4+ 12/89^2+ 4/91 56 5+ 10" PS4 236 11/85 5+ 11/89^3+ 5/91 62 5+ 10'' PS6 20 1/84 5+ Defaulted 4/91 44 5+ 10' P

Maximum score of skin smears taken from 6 sites.'' Refers to the incubation period of appearance of relapse from stopping chemotherapy. Date of relapse defined

as the midpoint between dates of the last examination without relapse and the first examination with evidenceof relapse.

Results of mouse foot pad inoculation: no. of mice showing multiplication of M. leprae/no. of mice harvested.

" ND = Not done.' I' — Pending.

of the last examination without relapse andthe first examination revealing evidence ofrelapse. The mean values were comparedby Student's t test.

RESULTSFollow up and relapses. Among the 384

cases followed up more than 1 year, the meanduration of follow up was 63.0 ± 30.3months after completion of treatment (Ta-bles 1 and 4). It varied widely among pa-tients treated with different regimens, rang-ing from 41.9 ± 12.1 months among patientstreated with WHO/MDT to 123.1 ± 23.3months among patients with Regimen B.Urine analysis for DDS was negative formore than 90% of the examinations, sug-gesting that the great majority of these pa-tients had indeed stopped chemotherapyduring the period of follow up.

After stopping chemotherapy, the major-ity of patients showed continuing clinicalimprovement as well as a declining BI, re-gardless of the regimens they had received(Tables 2 and 3). In fact, 113 cases (nearly30% of those followed up) reached smearnegativity during the follow-up period.However, by the end of May 1991 (as shown

in Tables 2 and 3) new lesions, mainly nod-ules and/or lepromas, together with highbacterial loads in terms of BI and LOGAFB,had occurred in 68 cases, suggesting thatthese patients had relapsed. In the histo-pathological examinations of these 68 pa-tients, relapse was highly suggested in 27 ofthem by the appearance of young histiocyticgranulomas containing numerous solid-staining bacilli either isolated or in globi.

As shown in Table 2, viable organismswere detected and, therefore, relapse wasconfirmed in 54 (88.5%) of the first 61 casesof suspected relapse for which the results ofmouse foot pad inoculation are available.Although, as shown in Table 3, the organ-isms from the remaining 7 cases failed tomultiply in mice, this proportion of casesin which multiplication could not be dem-onstrated is similar to that observed amongpreviously untreated cases (6, 12, 17 , .) There-fore, failure of the organisms to multiply inmice does not exclude relapse in these cases.Of the additional 7 patients suspected ofhaving relapsed, the results of mouse in-oculation from 5 cases are still pending, andmice were not inoculated with organismsfrom 2 cases when relapses were suspected

530^ International Journal of Leprosy^ 1992

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60, 4^Marchou.v Chemotherapy Study Group: MB Relapses^531

because of a lack of animals. Because, as isalso shown in Table 3, the clinical and his-topathological manifestations and the num-bers of organisms did not differ significantlyfrom the corresponding features of the 54cases whose relapses were confirmed (seeTable 2), relapses of the 7 cases should alsobe diagnosed. In brief, all 68 suspected re-lapses may be taken to have been con-firmed.

Relapse rates among patients treated withvarious regimens. As shown in Tables 1and 4, the overall relapse rate among 384patients was 17.7%, ranging from 2.9%among the patients treated with WHO/MDTto 27.8% among those treated with regimenA, and was no less than 15% among thepatients treated with 9 of the 12 regimens.Although the relapse rate among patientstreated with WHO/MDT did not differ sig-nificantly from those among the patientstreated with Regimens A2, E2, S6 and RPC(p > 0.05), it was significantly less than thoseof patients treated with Regimens A, B, C,REC, RED, RPD and S4 (p < 0.05 or <0.01).

The relapse rate per 100 patient-years ofobservation for all 384 patients was 3.4,ranging from 0.8 for WHO/MDT to 6.9 forRegimen S4. The rate in patients treatedwith the WHO/MDT was significantly lessthan that in patients treated with RegimenS4, but did not differ significantly from therelapse rates among the patients treated withany of the other regimens.

No correlation was observed between therelapse rate and the duration of RMP ad-ministration. As shown in Table 1, 50(17.7%) of the 283 patients treated withRMP for 3 months or less relapsed; whereas18 (17.8%) of the 101 patients treated withRMP for longer than 3 months relapsed.

Incubation period of relapse. No relapseoccurred during the first year after stoppingtreatment among the 384 patients followedup more than 1 year and the 42 patientsseen only during the first 12 months aftercompletion of treatment. Among the 68 pa-tients whose relapses were confirmed, themean interval between stopping treatmentand the appearance of the relapse, i.e., theincubation period of relapse, was 58.4 ±25.1 months, ranging from 27 months inthe patient treated with WHO/MDT to 94.0± 11.6 months among those treated with

Regimen A (Table 4); 32 relapses, nearly50%, appeared no earlier than 6 years afterstopping treatment. The overall cumulativepercentage of relapse appears to increaseregularly by about 3% per year from year 3to year 10 of follow up. On the other hand,the shorter the duration of RMP adminis-tration, the shorter the incubation period ofrelapse; the incubation period was 5 yearsfor 32 (64%) of the 50 relapses among pa-tients treated with RMP for Lc_ 3 months;whereas only 4 (22.2%) of the 18 relapsesamong patients treated with RMP for > 3months appeared within 5 years of stoppingtreatment (p < 0.01). In view of the cor-relations between the length of follow upand the risk of relapse, and between thelength of treatment and the incubation timeof relapse, the smaller relapse rate amongthe patients treated with WHO/MDT shouldbe considered as only provisional.

BI upon completion of treatment and riskof subsequent relapse. Among the 197 pa-tients whose maximal BI was ^ 5+ uponstopping treatment, relapses occurred in 42(21.3%). Relapses occurred in only 25(13.6%) of the 184 cases whose maximal BIwas 4 +. The proportions of relapse differsignificantly between the two groups (p <0.05), suggesting that the risk of relapse wasgreater among the patients with higher bac-terial loads at the time of stopping treat-ment. Of the 384 patients, 113 achievedskin-smear negativity during the follow-upperiod and relapses appeared in only 8(7.1%) of these patients; whereas relapsesoccurred in 60 (22.1%) of the remaining 27Ipatients who did not achieve smear nega-tivity. Thus, the risk of relapse was signif-icantly smaller among those who achievedsmear negativity (p < 0.01). However,achievement of smear negativity does notguarantee that the patients will not relapse.

Drug susceptibility of organisms recov-ered from relapsed patients. The suscep-tibility to RMP of the Al. leprae recoveredfrom the skin biopsy specimens obtainedfrom 47 relapsed patients was measured byinoculation of mouse foot pads; 45 strainswere inhibited from multiplication by theadministration of RMP to the mice in aweekly dosage of 10 mg/kg body weight and,therefore, were susceptible to RMP. The or-ganisms recovered from patient no. 43 ofthose treated with Regimen S4 and from

532^ International Journal of Leprosy^ 1992

patient no. 11 of those treated with RegimenRPD multiplied in RMP-treated mice.However, in neither case could resistanceto RMP be confirmed by subinoculation:the organisms of no. 43 failed to multiplyin subinoculated mice while the organismsof no. 11 multiplied in all 10 subinoculated,untreated control mice but in none of the12 subinoculated mice treated with RMP.Therefore, it is difficult to conclude that thesetwo relapses were associated with the emer-gence of RMP-resistant Al. leprae.

The susceptibility to DDS of 34 of the 47strains was also tested and 6 (17 .7%) strainswere found resistant: 3 of low degree, 2 ofmoderate degree, and 1 of high degree. Oneof the six strains had been shown to be re-sistant to DDS before treatment with Reg-imen RPC. Because primar■, , resistance toDDS among previously untreated MB pa-tients in Mali has been well documented('s), it is likely that the remaining four strainswere also resistant to DDS before startingthe combined therapy.

DISCUSSIONAs in the case of other infectious diseases,

relapse after cessation of specific antimicro-bial treatment is a crucial parameter in as-sessing the long-term efficacy of chemo-therapy in leprosy. Thus far, very limitedinformation is available with respect to therisk of relapse after treatment with RMP-monotherapy ( 5 ) and RMP-containing com-bined regimens ( 3). Very few studies haveinvolved long-term follow up of patients af-ter stopping treatment with RMP-contain-ing combined regimens (`').

With the introduction of WHO/MDT ( 20),the treatment of many patients is stoppedwhile skin smears are still positive. As aresult, the demonstration of acid-fast bacilli(AFB) in skin smears alone is no longer suf-ficient for the diagnosis of relapse as it wasduring the era of DDS monotherapy. There-fore, relapse may now be diagnosed onlyaccording to more stringent criteria: a) in-crease of the BI by 2+ over the previousvalue from any single site of old lesions andconfirmed on reexamination; b) occurrenceof definite new lesion(s) which demonstratea higher BI than do the preexisting lesions;and (c) demonstration of viable Al. leprae,an indicator of bacterial remultiplication,

by inoculation of mouse foot pads. How-ever, because the facilities for mouse inoc-ulation are not accessible in many leprosycontrol programs, and because in the pres-ent study viable organisms were demon-strated in nearly 90% of the patients, ful-filling the first two criteria, we believe thatthese two criteria are sufficient for the di-agnosis of relapse under field conditions. Intheory, relapse may occur in the absence ofobvious new lesion(s) during its early stagebut, in our experience, new lesions mustoccur sooner or later in real relapse. Becausethe quality of skin smears is far below de-sirable in many leprosy control programs,if the increase of the B1 is marginal and isnot accompanied by new lesion(s), we pro-pose that the patient be kept under closesurveillance, and the examinations repeatedevery 3 to 6 months. After all, relapse is nota clinical emergency, and there is no needto make a quick decision.

After the first few doses of treatment withRMP, the Al. leprae• of virtually all patientslose their infectivity for both immunocom-petent mice ( 2 ' 15 ) and immunosuppressedrodents, e.g., thymectomized and irradiatedmice ( 17) and neonatally thymectomizedLewis rats ( 4 ). However, one must be carefulin interpreting the clinical significance ofthese findings. Because of the insensitivityof the animal systems, including even theathymic nude mouse, one may measure atbest only the initial killing of 5 "logs," i.e.,killing of the first 99.999% of the organisms;whereas the untreated lepromatous patientsmay harbor as many as 10'" viable AI. leprae(`'). In other words, after his/her organismshave lost infectivity for mice, such a patientmay still harbor 10' viable bacilli, still asubstantial number. It is not relevant to dis-cuss whether or not these remaining viableM. leprae represent the "persisters" ( 47 ) be-cause the key issue is that they are capableof causing relapse, as shown by the resultsof the present study. Relapse occurredamong 17.7% of the patients after stoppingtreatment with a variety of RMP-containingcombined regimens, clearly indicating thatthey received insufficient treatment.

Another important result of this study isthat the relapses occurred late after stoppingtreatment. As shown in Table 4, the meanincubation period of relapse was about 5 ±

60, 4^Marchoux Chemotherapy Study Group: MB Relapses^533

2 years, with the relapses appearing earlieramong those receiving the shortest periodsof treatment with RMP (Table 1). The lateappearance of relapses confirms the as-sumption that the annual risk ofrelapse var-ied according to the length of time sincecompletion of treatment (n). Because, in ourstudy, relapses occurred at about the sametime as that recorded after RMP-monother-apy ( 5), it appears likely that the late ap-pearance is a characteristic of the relapsesafter treatment with RMP. In addition, be-cause the mean incubation period of theobserved relapses was close to the mean du-ration of follow up in each group (Table 4)it leads to the suspicion that more relapseswill occur as the follow up is prolonged, andthe mean incubation period of relapse maybe longer than that presented in Table 4.Because of the late appearance of relapses,patients should be followed up for at last 7to 10 years after completing chemotherapy.Only after a prolonged period of follow upmay one draw final conclusions with respectto the efficacy of any RMP-containing com-bined regimen.

The total relapse rate among the patientstreated with the 11 regimens other thanWHO/MDT was greater than 5%, and wasat least 15% among those treated by nine ofthe regimens. To date, no consensus hasbeen reached with respect to what repre-sents an acceptable relapse rate, and theopinions of clinicians may differ from thoseof epidemiologists. We believe that, at leastin clinical trials, a relapse rate to be ac-ceptable must be lower than 1.0 per 100patient-years. By this criterion, all of theregimens tested, with the exception of WHO/MDT, yielded unacceptable rates of relapse.However, the mean duration of follow upof the patients treated with WHO/MDT wasthe shortest (41.9 ± 12.1 months) amongthe 12 groups; whereas the mean incubationperiod of the 68 relapses was 58.4 ± 25.1months after stopping chemotherapy, andwas 94.0 ± 11.6 and 88.8 ± 21.4 monthsamong patients treated with Regimens Aand B respectively. Therefore, the relativelow relapse rate among patients treated withWHO/MDT must be interpreted with greatcaution pending longer follow up. Becausemillions of leprosy patients have been orcurrently are being treated with the WHO/

MDT regimen, we strongly suggest that theMB patients, especially those whose BI isstill high after completion of treatment, beclosely followed up.

Because 50% of the patients had been lostto follow up 5 years after completion oftreatment, and because of the late appear-ance of relapse, the observed relapse rate(17.7%) may well represent an underesti-mate. On the other hand, our results dem-onstrate that the risk of relapse is greateramong those patients whose BI is higher atthe time of stopping treatment. Because thegreat majority of our patients had a high BI,with more than 50% showing a maximal BI

5+ when stopping treatment, this situ-ation is quite different from that encoun-tered in many control programs, and it maybe that the high relapse rates observed inour study will not be observed elsewhere.

Finally, in contrast to the earlier findingsthat 22 of the 39 strains of M. leprae re-covered from patients relapsing after treat-ment with RMP monotherapy were resis-tant to RMP ( 5), almost all of the strainsisolated in the current study were demon-strated to be susceptible to RMP. There aretwo possible explanations. First, the strengthof the RMP component in some of the reg-imens was insufficient to select for the mul-tiplication of RM P-resistant mutants ('), andsecond, the companion drugs in other reg-imens prevented the selection of RMP-re-sistant mutants.

SUMMARYDuring the decade between the mid 1970s

and the mid-1980s, 12 rifampin (RMP)-con-taining combined regimens were testedamong lepromatous leprosy patients in theInstitut Marchoux. The 384 patients whowere seen at least once during the periodbeginning 12 months after completion oftreatment were considered eligible for anal-ysis of the relapse rate. By the end of May1991, relapse, manifested by a significantincrease of the bacterial index (BI) and theappearance of new lesions with a BI greaterthan that of preexisting lesions, had beenobserved in 68 (17.7%) of these patients.Relapse was confirmed by the presence ofviable Mycobacterium leprae in skin biopsyspecimens obtained from 54 of the first 61cases; virtually all of the isolated strains re-

534^ International Journal of Leprosy^ 1992

mained susceptible to RMP. The relapsesoccurred late, about 5 ± 2 years after stop-ping treatment; the shorter the duration ofRMP administration, the earlier the ap-pearance of the relapse. The variations ofthe relapse rate among regimens were con-siderable: total relapse rate ranged from 2.9%to 27.8%, and the relapse rate per 100 pa-tient-years of observation ranged from 0.8to 6.9. Among the 12 regimens, only theWHO/MDT yielded an acceptable relapserate (defined as a rate lower than 1.0 per100 patient-years). However, because themean duration of follow up was shortestamong the patients treated with WHO/MDT, the relative low relapse rate amongthese patients must be interpreted with greatcaution.

RESUMENEntre mediados de los 1970 y mediados de los 1980,

se probaron 12 esquemas de tratamiento combinado

conteniendo rifampina (RMP), en los pacientes con

lepra lepromatosa del Institute Marchoux. Trescientos

ochenta y cuatro pacientes que completaron el trata-

miento fueron seguidos para establecer su frecuencia

de recaida. A finales de mayo de 1991, 68 pacientes

(17.7%) habian ya presentado recaidas. Las recaidas Scmanifestaron como un ircremento significativo en el

indice bacteriano (IB) y como aparición de nuevas le-

siones con IB inayores que los de las lesiones preexis-

tentes. Las recaidas tambien se confirmaron por laspresencia de M ycobacterium !twat' viables en las biop-sies de piel obtenidas de 54 de los primeros 61 casos;

practicamente todas las cepas aisladas permanecieronsusceptibles a la RMP. Las recaidas ocurricron tarde,

despues de 5 ± 2 afios de suspender el tratamiento;mientras más corta fue Ia duracifin del tratamiento,

más temprana fue la apariciOn de la recaida. Las va-riaciones en la frecuencia de recaidas entre los dile-

rentes esquemas fueron considcrables: la frecuencia to-tal de recaidas osciló entre 2.9 y 27.8%, y el grado derecaidas por 100 paciente-afios de observación estuvo

entre 0.8 y 6.9. Entre los 12 esquemas de tratamiento,

solo la poliquimioterapia recomendada por la OMS

condujo a un grado aceptable de recaidas (menor de1.0 por 100 paciente-afios). Sin embargo, debido a qucla duración media de seguimiento fue mac corta en los

pacientes tratados con el esquema de la OMS, la re-

lativamente Baja frecuencia de recaidas en estos pa-cientes debe interpretarse con gran cautela.

RESUMEAu cours de la décennie s'étendant du milieu des

années 1970 au milieu des années 1980, 12 regimes

combines comprcnant de Ia rifampicinc (RMP) on etc

testes a I'Institut Marchoux chez des patients présen-

tam une lepre lepromateuse. Les 384 patients qui ontetc vus au moms une finis au cours de la periodecommencant 12 mois apres Ia fin du traiternent ont

etc consideres corn me eligibles pour l'analyse clu taux

de rechute. Fin mai 1991, une rechute, se manifestantpar une augmentation significative de l'indice bacterien

(III) et l'apparition de nouvelles lesions avec on 113 plus

&ley& quc celui observe au niveau des lesions pre-exis-tames, avail etc observée chez 68 (17.7%) de ces pa-

tients. La rechute etait conthmee par la presence de:Mycobacterium leprae viables dans des specimens debiopsie cutimee obtenus chez 54 des 61 premiers cas;

pratiquement tomes les couches isolees restaient sus-

ceptibles ft la RMP. Les rechutes apparaissaicnt tar-divement, environ 5 ± 2 ans apres l'arret du traite-

ment; au plus courte emit ('administration de RMP,

au plus precoce etait la rechute. Les variations du taux

de rechute entre les dillirents regimes étaient consi-&rabies: le taux total de rechute variait de 2.9% 0

27.8%, et le taux de rechute calcule pour 100 pesonnes-annees d'observation variait de 0.8a 6.9. Parmi les 12

regimes, scule la PCT telle que recommandee par l'OMSs'accompagnait d'un taux de rechute acceptable (défini

comme un taux inferieur a 1.0 pour 100 personnes-

années). Cependant, du fait que la durec moyenne dusuivi &Wit la plus courte parmi les patients traits par

la PCT/OMS, le taux de rechute relativement bas ob-

serve chez ces patients dolt etre interprété avec unegrande prudence.

Acknowledgment. This investigation received par-tial financial support from the UNDP/World Bank/

WHO Special Programme for Research and Trainingin Tropical Diseases.

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