Causes of failure of domicillary chemotherapy in pulmonary tuberculosis

Tubercle (1973), 54, 185

CAUSES OF FAILURE

OF DOMICILIARY CIIEMOTHERAPY TUBERCULOSIS

IN PULMONARY

By S. P. PAMRA,GOVINDPRASADand G. P. MATHUR from New Delhi Tuberculosis Ccntre, New Delhi-I. India

SUMMARY An attempt has been made to quantify the contribution of various factors, usually considered adverse, towards the failure of domiciliary chemotherapy in pulmonary tuberculosis. Results of 984 consecutive patients of bacteriologically confirmed pulmonary tuberculosis attending the New Delhi Tuberculosis Centre were analysed to provide information on this point. It appears that irregular treatment more than anything else is responsible for treatment failure. Initially extensive disease and/or poor general condition, drug resistance and advanced age, in that order, are other contributory factors. Initial drug resistance however does not contribute as much to failure as is sometimes believed. The prognostic significance of such factors as complications, tuberculous or non-tuberculous, and unsatisfactory treatment prior to reporting at a clinic could not be conclusively established.

RI&MI? Une tentative pour quantifier la contribution de divers facteurs, consider& habituellement comme defavorables, sur l’echec de la chimiotherapie a domicile dans la tuberculose pulmonaire, a Ctt faite. Les rtsultats obtenus chez 984 malades atteints de tuberculose pulmonaire confirmee par la bacteriologic, et s’ttant present6 consecutivement au Centre antituberculeux de New Delhi, ont et6 analyses dans le but d’obtenir une information sur ce point. 11 apparait qu’un traitement irrtgulier, plus que tout autre chose, est responsable de l’echec du traitement. L’ttendue initiale de la maladie et/au le mauvais &at general, la resistance aux mtdicaments et l’age avance sont d’autres facteurs qui contribuent 2tl’echec dans l’ordre cite. La contribution de la resistance initiale aux medicaments n’est pas cependant aussi importante que celle qui lui a Ctt parfois attribuee. La signification pronostique de facteurs tels que les complications, tuberculeuses ou non tuberculeuses, et qu’un traitement non satisfaisant reGu avant que le malade se presente a une consultation n’a pu @treCtablie de faGon concluante.

RESUMEN Se hizo una tentativa para cuantificar la contribution de varios factores, considerados en principio adversos, que influyen en el fracas0 de la quimioterapia domiciliaria de la tuberculosis pulmonar. Para este fin se analizaron 10s resultados de 984 pacientes con tuberculosis pulmonar confirmada asistidos en el Centro de Tuberculosis de New Delhi. B

186

PAMKA

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OTHEKS

Parece que la causa mas importante de1 fracas0 es la irregularidad en el tratamiento. Otros factores que contribuyen son la extension initial de la enfermedad y/o el ma1 estado general, la drogo-resistencia y la edad avanzada de1 paciente. Sin embargo, la resistencia bacteria na initial no es un factor tan influyente coma se ha creido hasta ahora. El significado pronostico de ciertos factores tales coma las complicaciones, Sean tuberculosas o no tuberculosas, y un tratamiento previo no satisfactorio, no puede ser aun establecido en forma concluyente.

ZUSAMMENFASSUNG Es wurde versucht, den EintW verschiedener Faktoren, die allgemein als ungiinstig gelten, auf das Versagen der ambulanten Chemotherapie der Lungentuberkulose zu bestimmen. Dazu wurden die Ergebnisse bei 984 laufend erfai3ten Patienten mit bakteriologisch bestitigter Lungentuberkulose, die das Tuberkulose-Zentrum in Neu-Delhi aufsuchten, analysiert. Es ergibt sich, dal3 unregelmlt3ige Behandlung vor allen anderen Faktoren ftir das Versagen der Behandlung verantwortlich ist. Anfanglich ausgedehnte Erkrankung, schlechte allgemeine Bedingungen, Arzneimittelresistenz und hiiheres Alter tragen in der gegebenen Reihenfolge ebenfalls zum Mit3lingen bei. Prim&e Resistenz ist jedoch weniger bedeutsam, als vielfach angenommen wird. Die prognostische Bedeutung von Faktoren wie spezifische oder unspezifische Komplikationen und unzulangliche Behandlung vor Aufsuchen des Zentrums 1ieDsich nicht zuverlassig ermitteln. Introduction

Chemotherapy makes it possible to achieve almost 100 per cent success in treatment of pulmonary tuberculosis under ideal conditions. In a routine domiciliary service, however, the conditions are seldom ideal and, therefore, the results are usually less good. This is often associated with several factors which are supposed to be the cause of treatment failure. An attempt has been made in this paper to study these factors and to quantify, as far as possible, their contribution to failure of treatment. Material

The paper is based on a retrospective analysis of 984 consecutive patients with bacteriologically confirmed pulmonary tuberculosis registered in the New Delhi Tuberculosis Centre in 1965 and 1966 from the domiciliary service area of the Centre and treated on a domiciliary basis. A list of 14 possible factors, some present at the start of treatment and others appearing during the course of treatment, was drawn up and the results of treatment were analysed in respect of these factors. For convenience of analysis, factors of a similar nature present initially and likely to influence the results of treatment in an identical manner, have been grouped together as follows :Group A - Disease involving 5 or 6 zones, large bilateral cavities and extremely poor general condition. Group B - Tuberculous or non-tuberculous complications e.g. diabetes, pleurisy, etc. Group C - Bacilli showing initial drug resistance to one or more of the first-line drugs (streptomycin, isoniazid, PAS and thiacetazone). Group D - Unsatisfactory treatment before reporting at the Centre, namely treatment with a single drug or with inadequate doses of two drugs. Group E - Age above 40 years.

CAUSES

187

OF FAILURE

The results of 525 patients newly diagnosed in 1966 were reported earlier (Pamra, Prasad & Mathur, 1971). To avoid small numbers in certain sub-groups, the patients freshly diagnosed in 1965 have been added for the present study. Further, the previous analysis suggested that higher age may be an additional adverse factor. In the present analysis, age above 40 years has therefore been included in the list of possible initial adverse factors. Treatment policy

The treatment policy in the Centre during the period was to start treatment of all sputumpositive patients with at least two of the four standard drugs (isoniazid with either streptomycin or PAS or thiacetazone). Some who had had treatment before coming to the Centre and whose treatment was inadequate, were given three drugs (usually isoniazid, PAS and thiacetazone) to begin with, modified subsequently in the light of the result of sensitivity tests, as far as possible. No patient was treated with ‘second line’ or ‘reserve’ drugs. The patients came and collected drugs from the Centre once a month. Surprise pill counting was not carried out as a routine and drug collection for purposes of this analysis has been taken as evidence of drug consumption. If a patient failed to attend within 3 days of the due date for drug collection, a health visitor visited the patient’s home. Three visits were paid to the home during the next 2 to 4 weeks if default contiued before a patient was finally listed as a non-cooperator. During the course of treatment, radiographical and bacteriological examinations, including culture and indirect sensitivity tests, were regularly repeated not less than once in 3 months, sometimes more frequently. As soon as the condition reached the ‘target point’ (sputum negative, no cavity seen in plain x-ray of the chest and the lesions radiographically stable for at least 6 months), companion drug or drugs were withdrawn and thereafter isoniazid alone was given for a further period of 12 months as ‘maintenance’ therapy. With this policy, treatment in most of the patients lasted 24 months and this duration has, though somewhat arbitrarily, been taken as adequate treatment for purposes of this analysis. Results Table I shows the frequency of the groups of adverse factors present at the start. It would be seen that 488, i.e. nearly 50 per cent, patients, had no adverse factor to start with. One hundred and fifty three patients had factors pertaining to more than one group and the remaining 343 had only one adverse factor at start of treatment. Bacilli in 17.5 per cent of the cases were initially resistant to one or more of the first-line drugs. TABLE L-FREQUENCY

OF ADVERSE FACTORS PRFSENT A’T START

.____-__

__~_

Patients Group

._--

No.

0, /O

‘A’ Initially extensive disease and/or

poor general condition ‘B’ Complications, tuberculous or non-tuberculous ‘c’ Initial drug resistance ‘D’ Unsatisfactory prior treatment ‘E’ Age over 40 years ‘0’ No adverse factor present at start __-.Total patients

96

9.8%

19 172 109 227 488

8.0% 17.5% 23.1% 49.6 “/,

984*

100.0 :<

11.1%

*Of those with adverse factors 153 had more than one factor and 343 only one factor.

IX8

PAMRA

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OTHERS

Table II shows the frequency of two adverse factors arising during the course of treatment. namely emergence of secondary drug resistance and the patient’s refusal to undergo surgery when advised. One hundred and sixty four patients whose cultures were sensitive to all four standard drugs to begin with, produced cultures resistant to one or other of these drugs at sometime during the course of treatment. TABLEII.--FREQUENCYOF AWERSE FACTORSARISINGDURINGCouastOF TREATMENT Length of treatment

Patients with sec0ndar.v drug resistance

Patients refirsiflg surgery

29 135

4 1.5

Less than 12 months 12 to 24 months

,

Total

The frequency of the two most important adverse factors arising during the course of treatment, namely irregular and inadequate treatment, are shown separately in Table III. Nearly 70 per cent of the patients (referred to as ‘Regular’ patients hereafter) took treatment with a regularity* of 80 per cent or more and 30 per cent with a regularity below 80 per cent (referred to as ‘Irregular’ patients). It may also be pointed out that the degree of regularity among patients who discontinued treatment at various stages was more or less the same as among those who completed 24 months’ treatment. However, among patients completing 24 months’ treatment, there were significantly less regular ones if one or more adverse factors were also present at the start (P
OF PATtEN~sCOMPLETINGSuccEsstvE PERIWS oc TREATMENT UP ‘ro 24 MONTHS No adverse fcctof m sturt

Patients at start

, Single udverse udverse fbctor nt sturt

Two or more rfdverse .fbctors rrt start

i

Tot&

153

100.0 “(,

Patients completing 3 months

Patients completing 12 months

*Regularity has been defined as drugs actually collected during any period as a percentage of the drugs that should have been collected during that period.

CAUSES

OF

189

FAILURE

An explanation is necessary for nearly 35 per cent of the patients dropping out before completing 24 months’ treatment. Table IV shows the main reasons for inadequate treatment. Nearly 4/5th of these patients were obliged to move out of the area before completing 24 months. This is a common observation in the clinics situated in large metropolitan cities in India. Many patients come from nearby towns and villages lookIng for better treatment facilities, stay with friends and relations in the big cities but as soon as symptoms have disappeared, they are obliged to go back home for social and economic reasons. Real non-cooperators who continued to live in the area but discontinued treatment against advice were only 6.7 per cent. The remaining 9.6 per cent stopped attending the Centre but took treatment elsewhere. It would also be seen from the same table that the percentage of patients moving out of the area is practically the same amongst patients dropping out after treatment for varying periods. TABLEIV.-REASONS FORPREMATURE STOPPAGE OF TREATMENT AT THECENTRE -. _.___~.. ____~. Period

bqfore treatment ~~l__

Less than 3 months

was stopped

3 to II months

12 to 24 months

Total No.

_-_

4’,

--

Patientsleavingthe area Patientscontinuingtreatmentelsewhere Noncooperative patients Total

81

61 16

136 9

91 8

288 33

s3.7”/; 9.6 “/,

4

II

a

23 __.-.-

rj.7V 0

344

100.0 “/,

23.5 O?

156

45.3%

107

31,10/,

TABLEV.-RESULTS OF 24 MONTHSTREATMENT OF PATIENTS HAVINGNO OR ONEADVERSE FACTORAT START: PATIENTS WITH REGULARITY OF 80% OR MORE

Adverse factor3 at start of treatment* 0 Treatment successful Treatment failed (but not dead) -_~

No. :/,

230 90.6 _____~

18

A

B

C

D

E

7 43.8

ia 78.3

22 62.9

13 81‘2

2 8.7

11 31.4

3 18.8

9 143

3 13.0

2 5.7

0.0

7 11.5

23 100.0

35 100.0

16 100.0

__--

No. 9/,

7.1

4 25.0

Dead

No. 0,0

6 2.4

5 31.2

Total

No. 9/,

254 100.0

16 100.0

45 73.8 .--

61 100.0

*For definition of groups see text.

RESULTSOF TREATMENT RELATEDTO ADVERSEFACTORS Table V shows the results of 24 months’ treatment of regular patients who had no or one adverse factor at the start of treatment. Treatment has been considered successful if the patient reached the ‘target point’ of treatment, and failure in all others whether dead* or alive. Whereas treatment was successful in 90.6 per cent of the patients if no adverse factor was present at the start, the treatment

190

PAMRA

AND

OTHERS

succeeded in only 43.8 per cent if the disease was very advanced or the general condition was verb poor to begin with (Group A). This difference is statistically significant (P < O$lOl).t The presence of initially drug resistant bacilli (Group C) also lowered the success rate significantly (P O-10) whereas that in group B (‘complications, tuberculous or non-tuberculous’) just falls short of statistical significance (0.05 < P < 0.10). Table VI shows the results of treatment in irregular patients having no or one adverse factor at the start. It is seen that if no adverse factor was present initially but the patient took treatment irregularly, the success rate came down from 90.6 per cent to 36.2 per cent, a difference which is highly significant (P < 0.001). Similarly, if in addition to irregularity another factor was also present the results obtained were considerably poorer than amongst regular patients with the same adverse factor. However, the number of patients in most columns is too small for any statistically valid conclusions to be drawn. TABLE W.--RESULTS OF 24 MONTHS TREATMENTOF PAIIENTSHAVING NO OR ONE ADVERSEFACTOR AT START: PATIENTSWITH REGULARITYOF BELOW d0 p; ._~ ~. Adverse factors

I /O

Treatment

A

I

No. 0’ /u

25 362

No. %

34 493

3 25.0

Dead

No. 0, 10

10 14.5

8 66.7

Total

No. 0, ‘”

69 100.0

12 IOO.0

successful _______ Treatment failed (but not dead) -___

___-

8.3 ____

at start of treatment*

B

C

3 42.91~~~_

4 21.0

fiat --_____. 4 57./t 7 /oo.o

8 42.1

D

E

4 so.oi

9 39.1

37.;I+

7 30.4

_~-.._~_..

7 36.8

,2.:-i_

7 30.4

19 100.0

8 100~0

23 IOOTJ

* For definition of groups see text. t Percentages based on less than 10 observations.

Table VII shows the results of treatment in 5 1 regular patients and 46 irregular patients who had two or more adverse factors at the start. The high failure rate is obvious and irregularity raises it significantly. It may also be mentioned here that if patients with adverse factors of groups B and D (no conclusive evidence regarding the significance of these factors could be found in the present study) are excluded from this table, the treatment in regular patients was successful only in 31 per cent of the patients and 46 per cent died, whereas amongst those who were, in addition, irregular treatment did not succeed even in a single case and 76 per cent died. Table VIII shows the results of treatment amongst those patients who had no ‘adverse factor’ at the start and completed 12 months but dropped out before completing 18 months treatment i.e. patients who could be considered to have had inadequate treatment. In this group, treatment was successful in 73.2 per cent of the regular and 41.2 per cent of the irregular patients. The difference in success rates of regular patients as compared to those who completed 24 months treatment regularly is highly significant (P
CAUSES

OF

191

FAILURE

TABLE VII.-RESULTS OF 24 MONTIB TREATMENT AMONG PATIENTS HAVINGTwo OR MOREADVERSE FACTORS AT START

Regularity 80% or more

No:-

Regularity below 80%

% _____

No.

%-

Treatment successful Treatment failed (but not dead) Dead

23 15 13

45.1% 29.4% 25.5%

4 17 25

8.7% 37.0% 54.3 %

Total

51

lOO.Oo,/,

46

100.0 %

TABLE VIII.-RESULTS OF PATIENTSWHO HAD 12 TO 17 MONTHS TREATMENT AND HADNO ADVERSE FACTORAT STARS

Regularity 80% or more No. %

Regularity below 80% No. %

Treatment successful Treatment failed (but not dead) Dead

30 5 6

73.2% 12.2% 14.7%

7 2 8

41*2:4 11.8% 47.0%

Total

41

100.0%

17

100.0%

time during the course of treatment. In 30 such regular patients who completed 24 months treatment, the treatment was successful only in 40.0 per cent; if no other adverse factor was present but in only 20.4 per cent if another initial adverse factor was also present. The rate of success amongst those who were irregular as well is naturally poorer still - hardly 5.0 per cent. It was shown in Table II that 19 patients refused to undergo surgical treatment when advised. Two of these did not complete 24 months treatment and both were failures. Of the 17 who completed 24 months, the treatment was not successful in any, though in two the sputum was converted while the cavities were still open. Two died and in the remaining 13 the treatment was a failure even though they were alive at 24 months. Although the numbers are small, yet they tend to show that failure to undergo surgical treatment at the opportune time again contributes very considerably towards ultimate failure of treatment. It would be interesting to see why the treatment failed in 24 patients who did not have an adverse factor at start of treatment and completed two years treatment regularly (Table V). In 20 out of these 24, treatment failure could be ascribed to secondary drug resistance and/or refusal of surgical treatment. In only 4 (2 of whom died) were none of the factors considered adverse in this study (either initial or emerging during the course of treatment) present to which failure could be ascribed. It is possible that some other unknown factor which was not included in this analysis could have been the cause of failure. There is however another possibility also. In this study, collection of drugs has been taken as synonymous with consumption of drugs. It is not unlikely that these 4 patients who collected drugs regularly all through did not consume them as they should have done. It may not be without significance that the cultures in these 4 remained sensitive throughout. Table X summarises the results of treatment in terms of death rates in patients with or without adverse factors. When two or more adverse factors were present and the patient did not take drugs regularly, the death rate was more than 50 per cent. If however, the patient took treatment regularly even with two or more adverse factors, the death rate was practically halved. If no adverse factor

192

PAMKA

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OTHEKS

was present and the drugs were taken cent. Irregular treatment alone sufficed

regularly for 2 years. the death rate was as low as 24 per to push this percentage up to 14.5. The results of treatment of the 903 patients who had treatment for 3 months or more are shown

in Table Xl.

Discussion

The analysis has shown that over 90 per cent success in domiciliary chemotherapy with the particular regimens used can be achieved if no initial adverse factor is present and the patients continue to take treatment regularly for two years. Of the initial adverse factors, very extensive disease, large bilateral cavities and extremely poor general condition are the most significant factors. Irregularity in treatment (regularity below 80 per cent) is another factor which contributes very considerably to failure of treatment. The study has also shown that initial drug resistance, of which so much is being made these days, does not in fact contribute so much to failure as some of the other factors like extensive disease and irregular and/or inadequate treatment. According to Fox (1972) initial drug resistance is relatively unimportant in deciding the success or failure of treatment and greater therapeutic gains can be achieved by improving organisational aspects of domiciliary treatment. Irregularity and inadequacy of treatment are far more important than initial drug resistance. Mitchison (1972) has calculated that if in a community initial drug resistance was present to the extent of 30 per cent. it would lead to only 5 per cent failures of treatment if a standard triple-drug regimen were used. If the influence of initial drug resistance on the outcome of treatment is not so important, the same cannot be said of acquired resistance. With the emergence of secondary drug resistance, the chances of treatment failing ultimately increase tremendously, with or without irregularity or other adverse factors. It was seen that the disease in almost all of these failures was cavitary and either the patients refused surgical treatment or it was not considered possible. In such a situation, doubt arises whether emergent drug resistance is the cause or merely an index of failure of treatment. Whether

TABLE IX.-PROGNOSIS

OF PATIENTS DEVELOPING SECONDARY DRUG RESISTANCEWHO COMPLETED24 MOWHS TREATMENT

Regularity 80 ?< or more

Treatment

successful

Treatment failed (but not dead) Dead Total patients

I

Regularity below 80 % No other adverse factor

Other adverse jhctor/s present

No othet adverse factor

Other udverse factor/s present

12 40.0 7; 16 2

10 20.4 ;j; 32 7

I

2

4,8 7; 18 2

5.7% 25 8

30 100.0 %

49 100.0 7;

21 1oo+l:/:

35 100.0 T/o

*Patients shown as dead in all the tables are taken as having completed 24 months’ treatment even though they may have died at any time during the 24 months. tThe two groups ‘Treatment failed but not dead’ and ‘Dead’ were combined for purposes of carrying out tests of significance if numbers in any of these cells were too small for a statistical test.

CAUSES

193

OF FAILURE

TABLEX.-ANALYSIS OF DEATHSACCORDINGTO PRESENCE OR OTHERWISE OF ADVERSEFACTORSAND REGULARITY OFTREATMENT ._~_.__ ~_.~ _____~..~ ____

No adverse factor

Regularity 80 S/, or more

Patientscompleting 24 months

Deaths

---_-

Single adverse factor ~_____

254

151

6 2.4 :,;

17 11.27;

Two or more adverse factors

Total

51

456

13 25.5 “,/,

36 7.9:;

Patients completing 24 months Deaths

Regularity below 80% ~~____-

69 10 14.5%

-______ Patients completing 24 months Deaths

Total

-. ~-.-

69

39.:;

323 16 5.0 7;

184

46

62 33.7:; __--.-.

54.5;

220 44 20.0 p/o

97 38 39.2 7;

-

640 98 IS.3 aI0

______.

TABLEXI.--RESULTS OF TREATMENT OF 903 PATIENTS WHO HAD TREATMENT FOR3 MONTHS OR MORE

Regular patients No. 7,; Treatment successful

468

74.5 “/o

Treatment failed (but not dead)

124

Dead Total

Irregular patients No. 1,;

Total No.

%

86

31.3%

554

61.4 74

19.7:;

127

46.2 %

251

278%

36

5.7:;

62

22.5%

98

10.8%

628

100.0 yj;

275

100.0 :/,

903

100.0 p/,

one or the other or both, association of secondary drug resistance with failure of treatment is unmistakable. Twelve or eighteen months treatment is sometimes recommended as adequate treatment. Probably it is not, at least for the type of cases on which this study is based. Among those who took 12-17 months treatment, results were significantly poorer than among those who took 24 months’ treatment. It, therefore, appears justifiable to recommend at least 2 years treatment with the regimens used in this study for patients who are sputum positive by direct smear. According to Fox (1968), severity of disease is relatively unimportant if potent chemotherapy regimens are used and has little influence on prognosis. This study has shown that, apart from irregularity in drug taking, extensive disease and poor general condition at the start of treatment contributed most to the failure with the regimens used. Age of the patients at the time of starting treatment is another factor which in this study seems to have influenced significantly the chances of success of treatment, though not to the same degree as extent of disease and regularity of treatment. Analysis of results of treatment in three clinics in USA (National Tuberculosis & Respiratory Diseases Association, 1971) showed that whereas sex, race etc. did not influence the results of

194

PAMRA

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OTHERS

treatment significantly, age and extent of disease did. The Singapore Tuberculosis Services/Brompton Hospital/British Medical Research Council Investigation (1971) also found an adverse influence of higher age and extensive disease. In conclusion, what is most important for success in domiciliary chemotherapy of pulmonary tuberculosis is early detection of cases, and regular and adequate treatment. REFERENCES Fox, W. (1968). Changing concepts in the chemotherapy of pulmonary tuberculosis. American Review of Respirator.,,

Diseases, 97, 767. Fox, W. (1972). General

considerations in the choice and management of regimens of chemotherapy for pulmonary tuberculosis. Bulletin of the International Union Against Tuberculosis, 41, 49.

MITCHISON,D. A. (1972). Implications

of the Hong Kong study of policies of sensitivity testing. BulIetin of the

International Union Against Tuberculosis, 47, 9. NATIONALTUBERCULOSIS & RESPIRATORYDISEASES ASXJCIATION(USA) (1971). A study of TB clinics in three areas. PAMRA, S. P., PRASAD,G. & MATHUR, G. P. (1971). Causes of Treatment Failure. In Proceedings of the 26th National Conference on Tuberculosis & Chest Diseases, Bangalore (India), January, 1971. p. 77. SINGAFQRETUBERCULOSJS SERVJCES/BROMPTON HOSPITAL/BRITISH MEDICALWEARCH COUNCILINVESTIGATION (1971). A controlled clinical trial of the role of thiacetazone-containing regimens in the treatment of pulmonary tuberculosis in Singapore. Tubercle. 52, 88.