Volume 54, Number IPrinted in the U.S.A.

INTERNATIONAL JOURNAL OF LEPROSY

Relapse Rates in Lepromatous LeprosyAccording to Treatment Regularity'

Joel Gerald Almeida, Kumar Jesudasan, Melville Christian,and Chinoy John George Chacko 2

Patients with lepromatous leprosy maynow hope for a limited period of treatmentinstead of life-long therapy ( 14). The studyof relapses after skin smears become "neg-ative for Mycobacterium Ieprae" will helpdetermine the optimal duration of treat-ment. We therefore continued our previousanalysis of relapses among smear-negativelepromatous (LL) and borderline leproma-tous (BL) patients on dapsone (DDS) mono-therapy ( 2) to find out whether continuedtreatment during smear negativity has asmuch influence on relapse rates as previoustreatment during smear positivity.

Much data is available on the magnitudeof relapse rates among treated "multibacil-lary" leprosy patients (4 6-I 3 ), including thatfrom our own previous report ( 2). However,none of these studies considered the regu-larity of treatment during smear positivityseparately from that during smear negativ-ity.

MATERIALS AND METHODSThe well-documented leprosy control

program of the Schieffelin Leprosy Re-search and Training Centre (SLR&TC), Ka-rigiri, India, among the 450,000 inhabitantsof Gudiyatham Taluk in South India, haspreviously been described in detail ('). Themost relevant points alone are repeated here.The whole population in the area is regu-larly examined for leprosy. All known pa-

' Received for publication on 12 July 1985; acceptedfor publication in revised form on 4 November 1985.

= J. G. Almeida, M.B., B.S., Research Fellow, Di-vision of Laboratories, Schieffelin Leprosy Researchand Training Centre (SLR&TC); K. Jesudasan, M.B.,B.S., D.T.P.H., Ph.D., Associate Epidemiologist; M.Christian, M.B., B.S., D.T.M.&H., D.E.C.D., Head,Department of Epidemiology and Leprosy Control,SLR&TC, Karigiri 632106, Tamil Nadu, India. C. J. G.Chacko, M.D., Ph.D., Head, Division of Laboratories,SLR&TC, and Professor of Pathology, Christian Med-ical College Hospital, Vellore, India.

Reprint requests to Dr. Chacko.

tients arc registered for treatment, whichthey collect at monthly village clinics neartheir homes. Details on each patient arecarefully maintained in an individual pa-tient record.

All 1580 LL and BL patients residing inGudiyatham Taluk (area = 1320 km 2 ) werelisted on 31 December 1977 from the treat-ment register of SLR&TC, Karigiri. Datawere assembled for each patient, from thedate of registration up to 28 February 1981,from individual patient records; 157 of 1580patients had insufficient data. Of the re-maining 1423 patients (90.1%), all were in-cluded who had been smear positive andhad had at least two consecutive negativeskin smears at any time after registration;1008 patients satisfied these criteria.

DDS monotherapy was used throughoutthe study period, and smear-negative pa-tients continued on treatment. Smears weretaken annually from a minimum of fourskin sites: earlobe and chin on the right,forehead and buttock or thigh on the left.

"Relapse" is taken to mean the re-ap-pearance of M. leprac in the skin smears ofa smear-negative patient, excluding thosecases where a single bacillus was found atonly one skin site on an isolated occasion.The "period of smear negativity" for a pa-tient is defined as the single longest periodafter registration which started with, endedwith, and included only negative skinsmears. The sum of the periods of smearnegativity for a group of patients yields their"person-years of smear negativity." "Reg-ularity of treatment" during a stated periodis defined as the percentage of monthsthroughout the period during which the pa-tient attended a monthly village clinic tocollect tablets. Those who collected fewertablets were assumed to have ingested fewertablets, on the average, than those who col-lected tablets regularly. In the interest ofclarity, it was decided before analysis thattreatment regularity during smear negativ-

16

Dura-tion ofsmearnega-tivity(yrs)

Treat-mentregu-larity

duringsmearnega-tivity

54, 1^ Almeida, et al.: Relapse Rates in LL^ 17

ity should not have class intervals identicalto those for regularity during smear positiv-ity.

"DDS-resistant infection" (') had beendiagnosed among patients whose annual skinsmears showed a continuing increase in thenumber of bacilli, despite > 50% regulartreatment overall. Some patients withenough bacilli [bacterial index (BI) ,̂ 2+ ]

for successful inoculation of the mouse footpad were also tested for the presence of DDS-resistant bacilli ( 3).

The chi-squared test with correction forcontinuity was used to determine the sta-tistical significance of observed differences.

RESULTSThe lowest relapse rate during the initial

three years of smear negativity was foundamong the patients with the better treat-ment regularities during both past smearpositivity and smear negativity (The Table).For example, until the third year of followup, patients with a history of less regular( 66.7%) treatment during past smear pos-itivity had 4.9% relapses per year (17 + 11 =28 relapses during 279 + 288 = 567 person-years of smear negativity); whereas thosewith more regular (>66.7%) treatment hadonly 2.8% relapses per year (26 relapses dur-ing 946 person-years). The difference is sta-tistically significant (p < 0.05).

A striking finding, however, is that fromthe fourth year of follow up onward, pa-tients treated more regularly during pastsmear positivity did not have lower relapserates than those treated less regularly. Onthe other hand, more regular (>75%) treat-ment during smear negativity was consis-tently accompanied by lower relapse ratesthan less regular ( - .75%) treatment evenseven or more years after the attainment ofsmear negativity (The Figure).

Patients with >75% regular treatmentfrom the seventh year of smear negativity(The Table) had 1919 (551 + 1378) person-years of observation. Twenty patients re-lapsed, giving a relapse rate of 1.0% per year;16 of these patients eventually became smearnegative again while continuing on DDSmonotherapy. Two of the remaining pa-tients were demonstrated to harbor DDS-resistant bacilli by the mouse foot pad test( 1 . 3); one of whom showed a continuing in-crease in bacilli in successive skin smears

THE TABLE. Relapses among smear-neg-ative LL and BL patients by regularity oftreatment during smear negativity and reg-ularity of treatment during smear positivity.

Treatment regularity duringsmear positivity"

>66.7%

1-3 ^ 75% 17/279 (6.1%) 9/191 (4.7%)>75% 11/288 (3.8%) 17/755 (2.3%)

4-6 ^ 75% 10/209 (4.8%) 6/123 (4.9%)>75% 1/206 (0.5%)h 9/521 (1.7%)

>7 <75% 13/557 (2.3%) 8/297 (2.7%)>75% 4/551 (0.7%) 16/1378 (1.2%)

a Number of patients relapsed/person-years smearnegativity.

b Significantly less than Lc75% treatment regularityduring 4-6 years of smear negativity; p < 0.005, chi-squared test.

and, hence, was diagnosed to have DDS-resistant infection (').

DISCUSSION"Relapses" in lepromatous leprosy can

occur due to "endogenous" Al. leprae fromwithin the patient, or "exogenous" Al. lep-rae from external sources, or both. Duringthe initial three-year period of follow up,more regular treatment during past smearpositivity was associated with lower relapserates. Perhaps inadequately treated Al. lep-rae resume multiplication and manifest asa relapse within this initial period of smearnegativity. Beyond this period, relapse ratesare no lower for the patients treated moreregularly in the past than for those with lessregular past treatment.

Relatively regular treatment during smearpositivity seems to have no salutary effecton the risk of relapse after the third year ofsmear negativity. Perhaps this is because"endogenous" AI. leprae (from within thepatient) do not pose as great a threat as "ex-ogenous" bacilli after the third year of smearnegativity.

Beyond the initial period of smear neg-ativity, the risk of "endogenous" Al. lepraemultiplying should tail off, and relapse ratessimilarly tail off, unless "exogenous" sourcesof Al. leprae (outside the patient) are avail-

1 8^ International Journal of Leprosy^ 1986

1-3 years^4-6 years^3 7 years

Duration of smear negativity

THE FIGURE. Relapses among smear-negative LL and BL patients by regularity of treatment during smearnegativity and smear positivity.

able. In the one non-endemic area wheretreatment was stopped after using four drugsfor a period ( 7), none of 80 LL and BL pa-tients with negative smears had relapsed.The risk of relapse from "endogenous" M.leprae may have been minimized in thatstudy by the use of four drugs. However,the low (possibly zero) relapse rates are con-sistent with the view that few "exogenous"M. leprae were available in that non-en-demic area.

The frequency with which "exogenous"sources of M. leprae may lead to detectablebacilli in the skin of an individual was partlymeasured by a total population study of ap-parently noninfected persons in a leprosy-endemic area ( 5); 5.8% of about 7000 per-sons with no sign of leprosy were found toharbor acid-fast bacilli in the skin of oneearlobe. The corresponding figure amongpatients with apparently "resolved" leprosywas 13.33%. That these bacilli were M. lep-rae was suggested not only by their failureto grow on routine mycobacterial media but,more strongly, by the higher-than-averageincidence of subsequent clinical leprosy

among the apparently noninfected personsharboring the bacilli.

One interesting group in the present studyis the 20 patients who "relapsed" after hav-ing been smear negative for seven or moreyears, despite >75% regular treatment dur-ing smear negativity (The Table). Althoughbacilli reappeared in their skin smears, 16of them went on to become smear negativeagain while on DDS monotherapy. DDS-resistant infection, therefore, seems an un-likely explanation of their transient smearpositivity. If "endogenous" M. leprae hadmultiplied to give the positive smears, thosepatients treated more regularly during pastsmear positivity should have a lower "re-lapse" rate than those less regularly treated.Instead, their relapse rate is at least as high:1.2% per year for those with more regular(>66.7%) treatment during smear positivitycompared to 0.7% per year for those withless regular ( 66.7%) treatment. This isconsistent with the explanation that the ba-cilli could have come from "exogenous"sources and were, therefore, unaffected byprevious treatment during smear positivity.

54, 1^ Almeida, et al.: Relapse Rates in LL^ 19

The rarity of DDS-resistant infection, oreven of sufficient bacilli to inoculate themouse foot pad, among the patients who"relapsed" after years of smear negativityis in keeping with our earlier studies ('). Wehad found that smear negativity indicateda significantly reduced risk of DDS-resistantinfection.

SUMMARYIn Gudiyatham Taluk, South India, 1008

lepromatous (LL) and borderline leproma-tous (BL) patients were studied. They hadpreviously been smear positive, had at-tained smear negativity, and continued onDDS monotherapy. "Relapse" was definedas the reappearance of ,Ifycobacterium lep-rae in skin smears. The area is endemic forleprosy.

The lower relapse rates in the first threeyears of smear negativity alone were asso-ciated with more-regular treatment duringboth past smear positivity and smear neg-ativity. From the fourth year of smear neg-ativity onward, only the more-regular treat-ment during smear negativity was associatedwith lower relapse rates; whereas patientswith more-regular treatment during pastsmear positivity had no lower risk of relapsethan those with less-regular treatment.

The finding that regularity of treatmentduring smear positivity seems to have noeffect on relapse rates beyond the third yearof smear negativity is discussed. In a lep-rosy-endemic area, it is argued that beyondthe first three years of smear negativity inan LL or BL patient, sources of M. lepraeoutside the patient may be more responsiblefor relapse than the patient's own bacilli.

RESUMENSe estudiaron 1008 pacientes lepromatosos (LL) y

lepromatosos intermedios (BL) en Gudiyatham Taluk,al sur de la India. Los pacientes que previamente ha-bian sido baciloscOpicamente positivos, alcanzaron lanegatividad baciloscOpica y continuaron con mono-terapia a base de dapsona (DDS). Sc consideri) quehubieron recaidas cuando reaparecieron bacilos en losextendidos de linfa cutanca. En el area cstudiada Ialepra es endemica.

Las bajas frecuencias de recaida en los primeros 3anos de negatividad baciloscOpica se pudieron asociarcon un tratamiento muy regular tanto durante Ia po-sitividad baciloscOpica previa como durante la etapade negatividad. A partir del cuarto anode negatividad,las bajas frecuencias de recaida solo se pudieron asociar

con un tratamiento muy regular durante la etapa denegatividad baciloscOpica. Los pacientes con un tra-tamiento muy regular durante la positividad bacilo-scOpica previa tuvieron igual riesgo de recaida queaquellos pacientes con tratamiento menos regular.

La regularidad del tratamiento durante la positivi-dad baciloscOpica no parece tener efecto sobre la fre-cuencia de recaidas despues del tercer ano de negati-vidad. Se argumenta que en un area con lepra endemica,las fuentes de Mycobacterium leprae externas son masimportantes que los bacilos del propio individuo comocausa de recaida en un paciente LL o BL despuês deltercer alto do negatividad baciloscOpica.

RESUMEOn a etudie 1008 malades lepromateux (LL) et le-

promateux dimorphes (I3L), dans le Gudiyatham Ta-luk, en Inde du Sud. Ces malades avaient etc ante-rieurement bacteriologiquement positifs; ils etaientnegatifs au frottis cutane, ils etaient toujours sousmonotherapie par Ia DDS. Les "recidives" ont etc de-finies comme la reapparition de .1f ycobacteriutn lepraedans les frottis cutanes. Cette region est ende.miquepour la lepre.

Un taux reduit de recidives au cours des trois pre-mieres annees a bacteriologic negative etait associe avccun traitement plus regulier avant la nêgativation, tantau cours de la periode precedente de bacteriologic po-sitive, qu'au cours de la pet -lode caracterisee par unebacteriologic negative. A partir de la quatrieme anneeA bacteriologic negative, et au cours des annees sui-vantes, l'abaissernent du taux do recidive n'etait as-sociee qu'avec un traitement plus regulier au cours dela periode negative. Les malades ayant poursuivi leurtraitement de maniere plus reguliere au cours de laperiode a bacteriologic positive, ne presentaient pas untaux de recidive plus faible que crux qui avaient eu untraitement moins regulier au cours de cette periode.

On discute cette observation que tend a montrer queIa regularite du traitement au cours de la pt.:6°de debacteriologic positive semble n'avoir aucun effet surles taux de recidives au-dela de la troisieme annee debacteriologic negative. Dans une region endemique pourla lepre, on pout defendre l'hypothese qu'au-deli destrois premieres annees de bacteriologic negative chezdes malades LL ou BL, les sources de M. leprae ex-terieures au malade peuvent etre davantage respon-sables pour les recidives que les bacilles du malade lui-meme.

Acknowledgments. We thank all of the staff of theDepartment of Epidemiology and Leprosy Control andthe Division of Laboratories, particularly Mr. J. Sam-uel. Mrs. Reeny S. Charles typed the manuscript.

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