A STUDY OF OPERATIONAL FACTORS INFLUENCING THE APPLICABILITY OF TWO REGIMENS OF SHORT COURSE CHEMOTHERAPY UNDER CONDITIONS OF AN URBAN TUBERCULOSIS PROGRAMME
Item
- Title
- A STUDY OF OPERATIONAL FACTORS INFLUENCING THE APPLICABILITY OF TWO REGIMENS OF SHORT COURSE CHEMOTHERAPY UNDER CONDITIONS OF AN URBAN TUBERCULOSIS PROGRAMME
- extracted text
-
Ind. J. Tub., 1989, 36, 213
A STUDY OF OPERATIONAL FACTORS INFLUENCING THE APPLICABILITY OF TWO
REGIMENS OF SHORT COURSE CHEMOTHERAPY UNDER CONDITIONS OF
AN URBAN TUBERCULOSIS PROGRAMME
P. Jaoota1, Sudha Xirasagar2, N. Parimala3 and K. Chaudhuri4
Introduction
An operational study of two regimens of Short
Course Chemotherapy (SCC) to assess their
efficacy
under
programme
conditions,
applicability in terms of initial acceptability, drug
default and adverse reactions due to drugs and
feasibility for District TB Programme (DTP)
Organisation was undertaken in an urban TB
Centre.
The operational efficacy of these two
regimens, namely 1SHRZ/7TH and 2SHR/6TH
was found to be 87% and 92% respectively. The
findings in detail have already been reported in
an earlier paper (Jagota et al; 1989). The various
factors i.e., initial willingness, drug default,
treatment completion pattern, adverse drug
reactions and initial drug resistance with their
potential harmful effects on the outcome of the
SCC regimens under study as well as work load
and extra cost these regimens entail for DTP
organisation arc discussed in this paper.
Objectives
(/)
Acceptability of two 8 month regimens in
terms of
(a) proportion of patients initially willing to
attend the clinic daily for 2 months,
(b) pattern of drug default among study
patients in intensive as well as in
continuation phase and defaulter
retrieval,
i
(c) treatment completion pattern.
'(r
(ii)
Is
The proportion of patients reporting
adverse drug reactions during treatment.
(Hi) Work load on the centre due to :
(a) administration of supervised treatment.
(b) taking of defaulter retrieval actions and
(c) management of adverse drug reactions.
(tv) Cost
(a) cost to the organisation,
(b) cost to the patient.
Material and Methods
Patients residing in Bangalore City limits and
attending Lady Willingdon State TB Centre
(LWSTC); of 12 years of age or more; with
pulmonary tuberculosis, whose sputum was
positive for acid fast bacilli on smear examination
and who had not received any previous anti-TB
chemotherapy-“core group”- were allocated at
random to two 8 month treatment regimens as
follows:
Regimen A : Streptomycin, Isoniazid,
Rifampicin and Pyrazinamide daily under
supervision for 1 month followed by isoniazid and
Thioacetazone daily self-administered for 7
months
given
as
monthly
collection
(1SHRZ/7TH).
Regimen B : Streptomycin, Isoniazid,
Rifampicin daily under supervision for 2 months
followed by Isoniazid and Thioacetazone daily for
self administration at home for 6 months given as
monthly collection (2SHR/6TH).
The usually recommended dosages were
prescribed. Patients with a history of previous
chemotherapy were termed as “Non-core group”
and allocated to these two regimens in a separate
random allocation.
Compensatory period of upto 15 days in case
of Regimen A and upto 30 days in case of
Regimen B was offered to the patient to complete
the missed doses of intensive phase, provided he
had completed at least 50% of due doses within
‘Chief Medical Officer, National Tuberculosis Institute, Bangalore; ’Medical Officer. National Tuberculosis
Institute, Bangalore; ’Statistical Assistant, National Tuberculosis Institute, Bangalore; ‘Director, National
Tuberculosis Institute, Bangalore.
A
aSii
*
©
|l
-r- v.-.,.^-..^-.
i.h,. .
. ...................
STUDY OF SHORT COURSE CHEMOTHERAPY
f. JAOOTA BT AL
UNDER URBAN TB PROGRAMME
215
214
“defaulter- «
in this study with the
d,e originally sriputeed period; olbc^e ha ™
excluded form the study.
free penod as well
dcfault was
Drug Default
The DTP
criterion to label a patient
Centre during the intake period (February
Table 1.
™
1984 w May 1985)
Total Sputum
^a8n0Be<i
Resident
Outside Bangalore
696
Resident
Bangalore City
1126
xx_
——[—
1—
Hot willing
695
Willing
431
1
I ------ZEZ
Untreated previously
321 ♦ 1*
Regimen A
Bxcluded
Study
23
127
X
Sefl.3.
94
study
138
x~ X
Resist
24
Unfit
21
.. -
Aged beloi
12 year
6
------ 3c----------- -
X
€
I
Treated previously
82
Neg.
9
Regimen B________
Excluded
53
admirustrabon/coUection on the day he was due.
The fir»t action was in the form of a letter posted
on the evening of the due date. The find action
consisted of a home visit on 4th day, if patient
failed to return for drugs.
Adverse drug reaction t
An adverse reaction was classified as minor if
it subsided with or without symptomatic
treatment, e.g. itching without rash, gastro
intestinal symptoms without evidence of clinical
jaundice or ulcer or joint pain without swelling.
An adverse reaction was classified as major
toxicity warranting modification of chemotherapy
in the eVent of development of clinical jaundice
intractable vomiting, rash, exfoliation, persistent
giddiness, etc.
Table 2. Reasons for unwillingness
Reason for unwillingness
No.
%
Total number of unwilling patients
695
1000
Unable to attend daily
539
77.6
Not prepared for daily injection
89
12.8
Wants to take treatment elsewhere
67
96
Initial Willingness
The initial acceptability rate of 38.3% is
applicable to Regimen B only, as all eligible
patients were asked for their willingness to attend
the Centre daily for 2 months, and allocation to
egimen A (1 month intensive phase) or
egimen B (2 month intensive phase) was made
later on.
Adverse drug reactions were recorded as and
when patient reported the same. At the time of
imtiation of treatment patient was informed to
report any untoward symptom experienced
during treatment.
Reasons for unwillingness
/7T%'?C 695 unwillin8 persons, a majority
(Z7.6%) were those who pleaded inability to
Results
attend daily for 2 months without specifying am
Classification of patients attending the Centre
parttcular reason. Refusal of SCC due’to daily
during intake period
injections accounted for 12.8% and 9.5% wanted
to take treatment elsewhere. (The acceptability of
Out of a total of 1,822 sputum positive TB
a fully oral self administered regimen is currently
patients diagnosed at the LWSTC during intake
, under study at N.T.I.).
penod (February 1984 to May 1985), 1,126 wcre^
residents of Bangalore City. Of these, 695 /
Old age influenced willingness adversely
adversely;
61.7%) were unwilling to attend the clinic daily
however, sex did not influence willingness (not
lor 2 months. Of the remaining 431 who were
shown).
willing, 21 were unfit for intake in the study on
Pattern of treatment completion
medical grounds; and 6 patients were below 12
years of age. Thus, 404 patients were classified as
Table 3 shows the pattern of treatment
either ‘'Core group” or “Non-core group" (321 F ■
completion of 321 patients with no history of
and 82 respectively). One patient was excluded
I
previous anu-tubercular treatment. There was no
Irom the study by mistake, on grounds of allergy
!
significant difference in overall pattern of
!<> Streptomycin.
.
treatment completion in the two regimens. The
Table 3. Partem of tiralment completion
□x_xz
Regimen A
No
%
Regimen B
No.
%
Total
No
|N" allocated
Sens.
107
Resist.
20
by mistake on grounds
-----* One patient was excluded
of allergy to Streptomycin.
Neg11
150
[No excluded
fN" eligible for continuation phase
I No made 80% of TIT in intensive phase
'<■ made 80% of TIT in continuation phase
of TIT in both phases
23
171
153
127
33
321
193
138
56
174
265
121
80.7
129
75.4
250
77.9
100
66.7
103
60.2
203
63 2
98
653
103
60.2
201
62 6
Il
P. JAGOTA CT AL
SIWY OF SHORT COURSE CHEMOTHERAPY UNDER URBAN TB PROGRAMME
217
216
of defaults made, rcgimeuwisc,
intensive phase, and the defaulter was retrieved
on 85% (390) occasions. In continuation phase
defaulter retrieval rate after letter posting was of
the order of only 52%. 293 defaults required a
home visit, as per protocol. However, 23 patients
reported for drugs when the team had just left for
home visiting and hence they were considered as
retrieved by letter posting and not due to home
visit. Of the remaining 270 defaults, on 69% of
occasions, patient responded to home visit (i.e.
they collected drugs within 10 days of home visit).
Home visiting became necessary mostly for
continuation phase defaults rather then intensive
phase (244 in continuation phase and 49 in
intensive phase).
or
completed optimum treatment.
Drug default and patient behaviour
Onset of default
uea^t^'Xlf X p^^on Rc^en
st
phase. They
number of doses of
“bSTd^res^cly, aker matog
each of the regimens.
ta a.tbMtio. pf‘.
O''*”11
patient was 15 and 1.7 respectively.
Response to defaulter action
A WU1 or 1,002 details were made
Reasons for default
1 to
sasses
ihroughout the treatment period.
Reasons for default were not elicited from
patients who reported for drugs within 4 days of
due date, as these reasons are often casual and of
little importance.
Reasons for the rest were elicited and
recorded during home visit. The moat frequent
reason turned out to bepatient going out of
station (52.9%) followed by patient being busy
with work (19.1%). Default due to relief from
symptoms accounted for 1.4% of defaults only.
Duration of default
On an average, a default during intensive
phase lasted for 2.2 days (i.e. a defaulting patient
attended for drugs approximately 2.2 days after
the due date) and 5.8 days in continuation phase.
Compensatory Phase
156 (59%) of 265 patients missed one or more
doses due to default and were eligible for
compensatory phase. However, a very small
number of patients required compensatory
period to complete optimum intensive phase
treatment (t 80% of doses), as shown in the Bar
Diagram.
Pattern of default
The distribution of patients
according to
He in intensive and continuation phase (Regimen-wise)
z r
fe''
S.
__________________________ ___ ________ _
Phase of chemotherapy Total Patents
0
Regimen A
■
1
Mean default
T
3
4
5+
7
4
1.1
mu
127
61
30
20
5
39
18
8
1.9
31
11
125
18
11
2.2
29
22
48
12
138
16
Intensive
1.7
14
7
133
33
Continuation
52
1
Intensive
Continuation
Regimen B
5 8:
COMFLtTtO
Number of defaults
26
Table
Chemotherapy phase
Total
Defaulter retrieval______________ ;------- --------No. of I actions (letters) taken
No. of II actions (home visits) taken
No. returned for drugs due to letter, after home vtsit
910
617
293
23
212
58
No. returned for drugs due to home visti
No. not returned for drugs_________
:; ?
mni'
.
INT. 7
CONT
385
49
476
232
244
5
37
18
175
434
7
wo
OOSf* VARta IN Itov. PHAtl
<"O Of FAULT)
rig. 1. Pattern of utilisatioi of compensatory phase to complete doses of INT phase, missed by default
STUDY QP SHORT COURSE CHEMOTHERAPY
p. JAGOTA et al
218
Drop-out from treatment
58 patients out of 265 dropped out of
treatmit altogether : 32 were lost to treament
24
or 7. 9% of patients on
RegimS A Sd 14 or 10.7% d
“
ReSen B) experienced major tanaty
w2ranted modification of chemotherapy.
7 in intensive phase and 25 »
nhase) while 26 could not be classified as lost as
dfey discharged *emsclves from tr^tment
during the last two months of chemotherapy.
The incidence of major tpxicity, according to
type is shown in Table 6.
Incidence of adverse reactions
Minor adverse symptoms were reported by 73
Table 6. Major tooc reactions
Continuation phase
Intensive phase
Toxic reactions
Gastro-intestinal
Regimen A
Regimen B
Regimen A
2
5
2
Vestibular
I
1
1
Hyper sensitivity
tn
Due to administration of drugs to patients under
analysis
Table 7. Work-load on centre
~
Total patients
fe.
No. of patients excluded
hI?
Doses per patient
I'
6
6
10
5
Total
Total
Regimen A
Regimen B
321
150
171
56
23
33
9
8
Category of work
It ■
ilO
5
3
2
Cutaneous
11
For 265 patients, 910 defaulter actions in the
Lform
0.™ of
°f letter
lCt.te.r posting
P051'"8 had to
t0 be taken
lakcn or on an
;«vcrage 3.4 letters to be posted per patient on
[treatment.
2.1
Default per patient
2.1
Defaulter action-I
12
Defaulter action-II
top .«r..»n)
Defaults per patient
Defaulter action-letter
st
No. of times reported
Avenge per patient
adverse symptoms reported by patients on cither
of the regimens.
All patients with’ adverse reactions including
jaundice were managed as outpatients, without
hospitalization.*
Cost
Cost of drugs to the organisation
The cost of these SCC regimens to DTP
organisation works out to Rs. 220/- per patient in
case of Regimen A and Rs. 268/- per patient in
case of Regnnen B.“ The exact organisational
cost of these regimens in terms of personnel,
Bme, etc cannot be calculated from this study
The relative costs of these regimens and
conventional DTP regimens are presented in
Table 8.
Table 8. Cost of different regimens perpatient to the
organisation
Regimen
1.
2.
Duration
(in months)
Cost
Rs
1SHRZ/7TH
(Regimen A)
8
220.00
2SHR/6TH
(Regimen B)
8
268.00
Study Regimens
DTP Regimens
TH(R1)
18
92.00
EH (R4)
18
346.00
Estimated cost to the patient for fully regular
treatment
Regimen
Cost
Rs.
No of visits
44.1
29.4
57.6
1SHRZ/7TH (Regimen A)
70.00
33
910
383
527
pue to adverse drug reactions
2SHR/6TH (Regimen B)
113.00
58
j Both major and minor adverse reactions were
^Ported on 387 occasions, 61% of them
Xxurrmg m intensive phase. Adverse symptoms
►us reqmred the attention of a doctor on about 2
^■ons for every patient on SCO regimen.
was no difference in the incidence of
18TH/18EH
35.00
18
138
3.4
3.4
1.1
Home visit
Adverse drug reaction
219
[ Home visits became r.e
necessary on 293
Pccasions or 1.1 home visit
—t per patient on
treatment.
127
265
Defaults
Average per patient:
In intensive phase of Regimen A, taking actual
treatment completion rates into account, on an
average, 29.4 doses of supervised treatment were
administered, and in case of Regimen B, 576
doses were administered to each patient.
Due to defaulter retrieval actions
Average per patient
No of patients under analysis
A,t„e.
per
(Table 7)
The 56 excluded patients (of both regimens)
made on an average 2.1 defaults per patient in
intensive phase, and had 8 and 11 supervised
doses per patient on the respective regimens. On
an average 1.2 home visits/patient (K defaulter
actions) were done for these excluded patients.
1
1
Twelve patients experienced major toxic
reactions, Le. intractable itching, itching with
rash, giddiness or jaundice all attributed to
Thioacetazone, in continuation phase. Most of
them, certainly those with cutaneous symptoms,
were changed over to EthambutoL There was no
exfoliative dermatitis.
Due to excluded patients
1
Joints
I
Work load on the centre
Regimen B
2
Jaundice
It may be noted that clinical jaundice in
ntensiyc phase developed in 2 patients only (both
on regimen A with the 4 drug intensive phase).
Arthralgia, a common feature of Pyrazinamide
toxicity was not encountered in this Study.
UNDER URBAN IB PROGRAMME
387
15
192
195
Cost to patient due to transportation
The average cost of transportation by bus to
the patient, works out to Rs. 70/- for Regimen A
and Rs. 113/- for Regii-thn B.
Vne excluded patient c----» calculated according to prices at which the’iuV
„s were procured by DGHS in 1987-1988.
STUDY OP SHORT COURSE CHEMOTHERAPY UNDER URBAN TB PROGRAMME
Selection of drug regimen
p. JAOCrTA ET AL
220
An informed decision to implement a new
treatment regimen in a programme will, thus,
require information on its overall applicability
measured in terms of outcome for the patient,
and organisational effort involved.
The regimens selected for the study had had a
record of almost 100% sputum conversion,
relatively low relapse rates of 7% and 6%
respectively and a low incidence of adverse
reactions under controlled clinical trial
conditions. On the other hand, their low cost and
short durations of 1 or 2 month supervised
intensive phase respectively, made them an
attractive proposition for large scale imple
mentation in a programme. The cost of both
regimens was approximately the same. However,
acceptability and operational efficacies of these
two regimens would determine which is more
robust and suitable for widespread use in a
programme.
Total Cues
82
I
I
|
Regimen B
|
Regimen A
"I
I
~1
K
Res.
12
Sens.
15
I
Excluded
6
Study
37
Excluded
6
Study
33
Initial willingness
Sens.
15
Neg.
6
of treatment
—————-——————
Final culture and sensitivity status
Neg.
3
Res.
19
1
2
3
4
Total
1
1
1
30
33
(57%)
1
2
6
16
25
2
1
3
9
47
61
Negative No.
%
Positive
Not examined
Total
Sputum conversion and relapses in previously
treated cases
1
Eighty two patients gave a history of previous
anti-TB treatment. Their classification according
to allocated drug repmen and initial culture
status is given in Table 9.
Considering both drug sensitive and resistant
patients together, 33 (57%) of 58 patients had a
favourable response to chemotherapy. By the
2
3
Discussion
The success or failure of SCC on a large scale
will depend largely upon initial acceptability and
patient compliance. Factors stich as distance,
frequency of visits required, motivation, doctor
patient contact, defaulter-retrieval actions, etc
would obviously influence patient compliance. In
addition, adverse reactions, both minor and
major, would influence acceptability of a regimen
to both doctor and patient.
,
i
[
I
E
|
E
i
I.
I
I
Initial low acceptability of about 40% is quite
disturbing and needs further exploration (It may
be noted that it applies to Regimen B only). This
order of refusal of these regimens could be due to
the abnormally rapid expansion of Bangalore city
requiring the patients to travel long distances to
reach the treatment centre. In this study the mean
distance a patient covered was 7 kms as
compared to 4 kms in a previous study of DTP
regimens conducted in 1973.3 Majority (84%) of
the refusals were due to inability to attend the
Centre daily for 2 months, or due to daily
injections. Thus, it would be reasonable to expect
that when largely unsupervised oral short course
regimens are offered to patients, requiring less
frequent visits to the centre, a majority of patients
would be willing for SCC. Significantly, only 6%
(66 of 1126) of urban patients, diagnosed at this
Centre in a metropolitan city, wanted to take
treatment from other sources, which included
Sanatoria, ESI, CGHS and other organised
health schemes. Further, only 6% (27 of 431) of
patients were judged unfit for these domiciliary
SCC regimens due to various reasons
emphasising the fact that about 95% patients can
be treated on an ambulatory basis.
I Hole of compensatory phase
I
The reason for offering a compensatory
221
treatment period was to help patients compensate
the missed doses of the crucial intensive phase
which is the period of maximum sterilization of
tubercular lesions. At the same time,
compensatory period could not be allowed to
patients whose compliance in the intensive phase
was very poor and, therefore, carried the risk of
multiple drug resistance due to wide spacing of
doses. Such an outcome would be disastrous for
the programme. Hence, it was offered only to
patients who had already completed at least 50%
of due doses within the originally stipulated
period. Majority of patients (88%) had already
completed 80% or more doses within the
originally stipulated period. Nevertheless, the fact
remains that the vast majority of patients could
complete nearly 100% of doses, owing to
provision of compensatory phase, and this could
have gone a long way in both sputum conversion
and prevention of relapse in these marginal
regimens, where the continuation phase of
Isoniazid and Thioacetazone for 6 to 7 months
was too weak to sustain an incomplete intensive
phase.
Drug default
Defaulting appears to be an inbuilt part of
human behaviour. In fact, it is naive to expect
100% compliance for entire duration of
treatment by merely giving instructions at the
time of initiating treatment.
In this study, while drug default was of quite a
high order, defaulter retrieval was also very high.
Letter posting, when a patient defaulted, was of
negligible cost considering that two thirds of
patients returned to treatment. Similarly, a home
visit on 4th day of default, mostly succeeded in
retrieving the remaining defaulters. At the same
time, it should be remembered that defaulter
actions become meaningless if accurate postal
address is not elicited at the time of opening a
treatment card. The work load due to defaulter
actions is within manageable limits of existing
DTP organisation. Provision of staff and means
of transportation for prompt home visit yielded
good results in terms of treatment completion.
These facts are again borne out by a
comparison between various settings of
chemotherapy.
Table 11 shows a variety of situations, from a
clinical trial situation of highly selected
“compliant” patients with many a staff to
miDY Of> SHOTT COUUE CHEMOTHERAPY UNDER URBAN th frcxmamme
-----------------Proportion ofpa&ttti making vario^
Chemotherapy atuation
<*
3
—
4*
4’
14D
8.7
165
0-13
275
17.0
105
0-5
0-13
In conclusion, domiciliary short course
chemotherapy proved feasible and advantageous
in an urban tuberculosis programme. Between
these two regimens, while Regimen A equalled
Regimen B in efficacy, it has operational
advantages over Regimen B. In fact, a regimen
with a 2 month intensive phase of four drug*,
largely self-administered would possibly improve
upon the initial acceptability and results observed
with these regimens.
08
Acknowledgements
2
-------Z--------- ,
No. of padert*
0
1
cohort. It should be remembered that a larger
proportion of previously treated cases could
substantially dilute the outcome.
Ran«e
Short course Chemotherapy
Cunent operational study
Int phase 1/2 months
Cont. phase 7/6 months
321
258
Bi-weekly phase 2 months
322
12.4
Clinical trial1
Daily phase 3 months
265
343
287
49.1
24.0
9»
5.9
11.1
183
34.4
28.4
16.4
7.7
13.1
Conventional DTP Regimens
1
Operational Study3
Self-administered daily Regimen (R,)
189
Bi-weekly supenrised Regimen (RJ
134
9.7
522
20.1
11.1
143
122
16.4
08
29.1
16.4
6.7
38.1
0-17
193
16.5
12.1
32.0
0-10
45.0
The authors are grateful to Dr G.VJ. Baily, former
Director, NTI, Bangalore, for guidance, to Mr M.V.
Jaigopa), Computer, NTI for Statistical assistance,
Mr B.K Keshavamunhy, former Sister Tutor, Mrs A.
Korah, Mrs V. Lalitha, Mr. BA. Eswara, Mr. N.
Narahari Rao, Health Visitors, Mr. Bashcer Ahemad,
Under Service PmffOtnme3
I ■
I''
12 Collections within 15months
Self-administered daily
1. KS. Aneja et al- Ind J Tub, 1962 29,19
2. GVJ. Rady « of-Ind JTub, 1974 21, 52
3. MA. Seetha et al - Ind J Tub, 1976,23 90.
of any patient with adverse symptoms - major or
S-r
IIi
motivate patients and retrieve
operational study conditions with vreU defined
effort for case-bolding, to a service
obliged to treat every patient diagnosed with
minor.
Drug resistance at the start of treatment
As was emphasised in the previous paper
(Jagata et al; 1989
1989),
many patients with history of
>-many
LXg periods of anti-TB treatment wil be
vm^g
as sputum
positive
y
positive
newnew
patients in
D^7yhclr
status
_sensitivity
__ ‘
i will not be
facility in DTP.
tQ lack of culture
-- »Adverse reactions
The outlook for such patients putt on SCC would
_j co:
constituted about
AOverse rcatw
interest- such patients
It has often been feared that adverse
lhii j^rt put on S
---- Among them,
SCC.
OTTO m
ow. r— —
"
in SCC, where M drugs are used t»
oc c«..v.«
e> organisms
44% turned
turned out
out to
to be
excreting
• - —Fifty
*«•- seven
----- —
7 cent ot toe
phase, would *riood^.'IS^1Ucncy
resistant to Isoniazid.
per
Dl LU
------ •
.
routine- programme conditions. Both frequency
with history of various pcnods
pcnods of anti-in
and severity of adverre symptoms
jSnent
sent had
had aa favourable
favourable re.
response to
seem quite manageable wuhm the ensfrng
^emotherapy. Thus, considering
chemotherapy. Thus,
work of DTP. There were 387 occasions
and untreated patients together, the
treated t—— —- patient required doctor's atfrn^ to-manage
overall sputum^^^tt
conversionwas
was 81%
817b (comparedto
(.comp**
adverse symptoms - on an average
90% ^^ersion
conversion in the culture sensitive group),
group).
per patient on SCC-Dre occurrence of ^undice
con
Thus, in this cohort, the proportion of
Kamern was a little over 1%
treated patients was too small to su^tan^
265). There was no care of afoliaiwe d^mabtotmfluenceAte outcome of SCC m the entire
variable availability of
for case-holding. In there three
a majority of patient, have defauhed°
patients in the chmcal tnal complete treatmc
owing to intensive defaulter actions.
■"S
223
Lab. Attendant, NTI, Mr Chaitanya Murthy and Mr.
Shamanna, Health Visitors of LWSTC, who
participated in the study and Mr. S. Nagaraj, artist for
drawings and Mr. P. Perumal for secretarial assistance.
The authors also acknowledge with gratitude the
assistance and support given by Dr. B.S. Nagaraja
Rao, Joint Director and Dr. E.V.V. Gupta, Deputy
Director, LWSTC, for the study.
REFERENCES
Jagota, P. « al. The acceptability and efficacy of two
regimens of short course chemotherapy under
conditions of an urban tuberculosis programme
Ind. J. Tub; 1989,36,18
G.VJ. Baity et aJ A concurrent comparison of an
unsupervised daily and a twice weekly regimen of
chemotherapy in a routine outpatient treatment
programme. Ind J. Tub. 1974, 21,153-167.
Third East African/BMRC (1980) Tubercle. 61
59-69.
151
ANTI-TUBERCULOSIS REGIMENS OF CHEMOTHERAPY
Ind. J. Tub , 1988, 35, 150
ANTI-TUBERCULOSIS REGIMENS OF CHEMOTHERAPY
Recommendations from the Committee on Treatment of the International Union
Against Tuberculosis and Lung Disease
1.0 Introduction
Short-course chemotherapy is now widely
accepted as the treatment of choice for pul
monary tuberculosis. A number of regimens
of chemotherapy have been shown in control
led clinical trials and in clinical practice to be
highly effective in many countries and in a
wide variety of patient populations and health
service conditions. From the resultsol cli
nical trials and of complementary laboratory
studies, the mechanisms of action of the main
antituberculosis drugs and their contribution
to regimens are also becoming increasingly well
understood. At its meeting in Singapore
in November 19S6. the Committee on
Treatment of the International Union Against
Tuberculosis and Lung Disease, following a
survey among its members, therefore, decided
to make specific recommendations on antituberculosis regimens and drug dosages to be
used in the treatment of adults and children
with active pulmonary or extra pulmonary
tuberculosis requiring chemotherapy.
dal, and although large doses of ethambutol
are bactericidal, the difference between a thera
peutically inadequate dose and a toxic dose is
small.
2 2 Sterilising Action
Rifampicin and pyrazinamide are the most
important sterilising drugs because of their
ability to k:ll semi-dormant bacilli capable of
surviving the bactericidal action of isoniazid
and so of giving rise to relapse after treatment.
The bacilli specifically killed by rifampicin are
probably bacilli which are dormant but sub
ject to transient favourable changes in their
environment and so to short periods of active
metabolism. The bacilli specifically killed by
pyrazinamide are probably those with their
metabolism inhibited by an acid environment.
.
those, for example, within macrophages and
■in areas of
------n------- T '
acute inflammation.
To achieve
maximum sterilising effect in 6-month regi
mens in the treatment of human pulmonary
tuberculosis, pyrazinamide need be given for
only the first 2 months but rifampicin throu
months, further evidence that
ghout the 6 months.
2.0 Drug Action
these two drugs arc uniquely active against
special components of the bacillary popula
The antituberculosis drugs vary in (1) their tion.
t|On
bactericidal action, defined as their ability to
kill large numbers of actively metabolising 2.3 Preventing the Emergence of Acquired
bacilli rapidly, (2) their sterilising action, de
Resistance
fined as their capacity to kill special popula
Even populations of tubercle bacilli which
tions of slowly or intermittently metabolising
have not been exposed to antituberculosis
semi-dormant bacilli : the so-called “pcrsis- drugs contain small proportions of drug-resis
ters”, (3) their ability to prevent the emer tant mutants
If inadequate drug combina
gence of acquired resistance by suppressing tions are used, these mutants are likely to
drug resistant mutants present in all large replace killed susceptible bacilli and give rise
bacterial populations, and (4) their suitability
to drug-resistant disease. The effectiveness
for intermittent use.
of drugs in preventing the emergence of acquir
ed resistance depends upon the extent to
2.1 Bactericidal Action
which they can inhibit bacilli continuously,
whatever their tatc of metabolism, even when
Most of the antituberculosis drugs, with there is some irregularity in drug taking. Iso
the exception of the bacteriostatic drugs niazid and rifampicin are the most effective at
thiacetazonc and PAS (para-aminosalicylic preventing the emergence of resistance to
acid), have some bactericidal action but
other drugs, and streptomycin and ethambutol
isoniazid is the most potent bactericidal drug. are only slightly less so Pyrazinamide is less
It has been estimated that isoniazid alone may effective, and PAS and thiacetazonc are the
kill some 90 per cent of the bacillary popula
tion in a patient's lesions during the first few least effective.
days of chemotherapy. Rifampicin is also an 2.4 Suitability for Intermittent Use
important bactericidal drug. Streptomycin
Isoniazid, rifampicin- pyrazinamide, strepand pyrazinamide arc less potently bactcrici-
----•Reproduced from Bulletin of the I.U.A.T.L.D., June 1988 issue.
■H
tomycin and ethambutol are all effective
when given 3 times or twice a week. Thiacetazone is less effective when given intermit
tently than when given daily.
3.0 Regimens of Chemotherapy
3.1 Recommended Regimen for Newly-Diagnosed Patients
In the treatment of newly-diagnosed
:ms, the
.uv regimen
---------- should include, whenpatients,
- _ — !LI*
■
the
main
sterilising
ever possible,
— -------— drugsand
those most effective at preventing the emerofnee- of resistance, namely isoniazid (H),
rifampicin (R), and pyrazinamide (Z) (Table1)
Isoniazid also reduces patients’ intectiinfectivity rapidly
because of its highly
' "t because
l/c";' effective
------bactericidal
action t^ni^id
Isoniazid and
and rffammcm
rifampicin
should be given daily for 6 months and pyra
zinamide in addition for the first 2 months or
8 weeks : 2HRZ 4HR.
w va
drug concentrations are not altered by the
combination.
The above 6-month daily regimen is now
standard and should be used in the treatment
of pulmonary and extra-pulmonary disease in
both adults and children. Because of its
uuimy U^
G) to cure patients rapidly (even the
^jlity.
majority of those who default after only 2 to
3 months of treatment). (2) to cure the great
majority of patients with strains of bacilli
initially resistant to isoniazid, streptomycin,
or both drugs, and (3) to prevent failure due
to the emergence of acquired resistance, it is
more cost-effective than cheaper and less
.....
- . u
uu.e.u
potent regimens (sueh as those which do not
include rifampicin
rifampicin or
or pyrazinamide), even in
include
developing countries.
of (hi? regimcn whjch
Fixed-dose combination preparations of
isoniazid, rifampicin and pyrazinamide. and
of isoniazid and rifampicin should be used
when available to aid compliance and to
reduce the risk of incorrect dosage, but it is
essential that only those preparations are
used for which bio-availability studies have
been carried out and have shown that serum
are equally effective and which, in some cir
cumstances, have advantages ■
3.1 1 Intermittent administration. In the
continuation phase, isoniazid and rifa!nf''c'n
may be given 3 times or twice a week : 2HKZ/
4H3R3, 2HRZ/4H2Ri. This has the advan
tage that the continuation phase can be admi
nistered on an outpatient basis under full
supervision, every dose being given under the
direct observation of outpatient health service
Table 1
Regimens of Chemotherapy
Recommended standard 6-month regimen
2HRZ/4HR
Variants of standard 6-month regimen
1
When fully supervised intermittent chemotherapy can be organised
2HRZ/4H3R:,
2HRZ 4H,R.
2E3H3R3Z3 4H3R3
2S3R3Z.3/4H3R3
2. When there is a high level of initial resistance
2EHRZ/4HR
OrltdXr S), where appropriate, to the initial phase of one of the variants
Alternative less potent regimens of longer duration
1 With a potent initial 4-drug phase
2SHRZ/6HT
2SHRZ'6SsH2Z2
2. With a less potent or no initial phase
2SHR/7HR
2EHR/7HR
9HR
2SHT/I0HT
2SHE/10HE
2SHP/10HP
2SAT/10S.H.
2SHP/10S2H2
S streptomycin;
H
T -thiacetazonc;
P
R
rifampicin;
Z
pyiazinanndc;
L
elbanibutol,
152
ANTI-TUBERCULOSIS REGIMENS OF CHEMOTHERAPY
staff or of a paramedical worker or lay person
who has been taught to supervise chemothe
rapy. In this way the level of compliance
is known and a high level can be encouraged.
Intermittency should not be used purely as a
cost-saving measure.
In programmes where chemotherapy is
administered throughout under full supervi
sion on an outpatient basis, the regimen may
be given 3 times a week from the start. When
this is done, either ethambutol or streptomy
cin should be added to the initial phase:
2E3H3R3Z3,4H3Rj. 28311^523'411^3, but sec
paragraph 8.4.
3.1.2 Populations with a high rate of initial
drug resistance. When there is a high rate of
initial drug resistance, or if it is suspected
that the patient’s strain is resistant to isonia
zid, it is desirable to add a fourth drug to the
initial phase of the regimen. Ethambutol is
a good fourth drug because initial resistance
to it is rare, but streptomycin may be prefer
red in some populations in the hope that it
will encourage compliance as it has to be
given intramuscularly (see paragraph 8 4).
Also, the orally administered drugs can be
given fully supervised at the time the strepto
mycin injections are given.
3.2 Alternative Less Potent Regimens
When optimum chemotherapy cannot be
used in a population or in individual patients,
one of the following alternative regimens may
be used. It must be appreciated, however,
that these regimens involve less potent drug
combinations than the recommended 2HRZ/
4HR regimen and its variants and. therefore,
have to be given for longer than 6 months.
They are inferior regimens which, although
in some cases cheaper purely in terms of
drug costs, are unlikely to reduce the total cost
per'patient
per patient cured. If it is decided to use one
of the alternative regimens, priority should be
given to the first two, both of which have a
highly potent initial 4-drug phase (SHRZ)
daily for the first 2 months.
2SHRZ/6HT—streptomycin, isoniazid, ri
fampicin, and pyrazinamidc daily for 2 months,
followed by isoniazid and thiacetazonc daily
for 6 months (total duration 8 months). Iso
niazid alone may be given in the continuation
phase if there arc problems with thiacetazonc
toxicity, but only if the level of initial resis
tance to isoniazid in the population is known
to be low.
2SHRZ/6S2H2Z2—streptomycin, isoniazid,
rifampicin, and pyrazinamidc daily for 2
months, followed by streptomycin, isoniazid,
and pyrazinamidc fully-supervised twice a
week for 6 months.
2SHR/7HR, 2EHR/7HR or 9HR—isonia
zid and rifampicin daily for 9 months, with or
without streptomycin or ethambutol in addi
tion daily for the first 2 months. 9HR should
only be used if the level of initial resistance to
isoniazid in the population is known to be
very low.
2SHT/10HT, 2SHE/10HE or 2SHP/10HP—
streptomycin, isoniazid, and thiacetazonc (or
ethambutol, or PAS) daily for 2 months fol
lowed by isoniazid and thiacetazonc (or
ethambutol, or PAS) daily for 10 months.
2SHT/10S2H2 or 2SHP/10s2H3—streptomy
cin, isoniazid, and thiacetazonc (or PAS)
daily for 2 months, followed by streptomycin
and isoniazid fully-supervised twice a week
for 10 months.
3.3 For Patients in whom Relapse has Occurr
ed after Chemotherapy
Relapse after chemotherapy is rare if the
recommended 2HRZ/4HR regimen or one of
its variants is administered regularly by an
efficient treatment service and the patient
complies and responds well during chemo
therapy. If relapse occurs in these circums
tances, or in a patient who defaulted after
only a short period of regular chemotherapy,
acquired resistance (or additional resistance
if the initial strain was already resistant) is
unlikely to have emerged, and the patient
should be retreated with the same drug com
bination. although for 9 rather than 6 months
and under stricter supervision.
If one of the less potent alternative regimens has been used, or if relapse has occurred in a patient whose chemotherapy (whatthc regimen) has been poorly supervised
ever the
and who has taken drugs irregularly for much
of the time, acquired...........
resistance
is more likely«
to have emerged and a careful assessment
must be made before a retreatment regimen
is chosen (see paragraph 3.4).
3.4 For Patients whose Primary Chemotherapy
has Failed
When there is no response to chemothe
rapy in a patient who is known to have taken
it regularly this is probably because of multi
ple resistance in the initial strain; and when
there is a bacteriological response at first,
followed by bacteriological failure whilst
chemotherapy is still being given (fall and
rise phenomenon), this is probably because
acquired resistance or additional resistance
ANTI-TUBERCULOSIS REGIMENS OF CHEMOTHERAPY
153
has emerged. In either case the regimen must
!5.0 Drug Dosages
be changed. But first it is necessary to try to
The recommended dosages for all the drugs
establish whether ’failure’ was in fact due
are shown in Table 2. These dosages are
simply to the patient's having failed to take
appropriate for all forms of tuberculosis (in
any chemotherapy or having stopped it pre cluding meningitis and miliary disease) and
maturely (see paragraph 3.3). Once it is
for children as well as adults There has been
clear that the patient is no longer responding
a tendency in the past to prescribe high dosa
to the prescribed regimen a careful assessment
ges for children, especially of isoniazid,
is necessary. A detailed drug history should
leading to needless adverse effects such as
be drawn up. including the drugs used, their
hepatitis.
dosage and duration of administration, and
6 0 Supervision of Chemotherapy
the compliance of the patient in treatment.
Sensitivity tests on the failure cultures may
Poor compliance by patients is by far the
be helpful, but only if they have been done
most important cause of poor results from
in a reliable laboratory undertaking good
potent regimens under programme conditions.
quality control.
The importance of complying in treatment
Whenever possible, the patient should be throughout the whole duration ol chemothe
retreated for at least 12 months from the rapy must be repeatedly emphasised to the
patient and his family, and whenever possible
time the
It
sputum OIIIVU'J
become
---------------------------negaUve.
O
rv*v.w... - --------- ---I
,
. ..aUUlUlll
• smears
daily
regimen
containing,
for the first every dose
of the regimen should be cldlYliniS*
USIOl^ 3 Ganj
ivjjun-u
vw...
—.-—-c?tered under full supervision In some coun
3 to 4 months, at least 3 drugs to which his
tries this can be achieved by medical service
organisms are likely to be sensitive : preferably
lnal he
nc has never
,lc,vl received
-------------------stafT on an entirely outpatient basis In others,
3, that
before
and which
do
not share cross-resistance
with any that he service staff can provide full outpatient superQai lll/l
----has, chemotherapy with at least 2 drugs then vision in the urban but not in the rural areas,
iua..v.. Unless
...................
being continuedu luC
thereafter.
it ts un while in others treatment is rarely, if ever,
drug
should not be fully supervised by service stall I f the service
avoidable. a single
s...D— new
-.
■
i* • 1 •
.if
....
c 11
f •/ict. \ it
n’lrnmpiiiadded to a previously failing or suspect stair cannot provide supervision, paramedi
regimen, because this will probably lead to cal or lay persons, including a member of
the emergence of further resistance- Il may. the patient’s family, can be taught to do so.
however.be done as a last resort when resis
It is wrong to assume that standards of
tance to all other available drugs is likely to supervision are necessarily better in hospital
have emerged.
than in outpatients. In general, patients
Rifampicin, ethambutol, and pyrazina should not be admitted to hospital, even for
midc (KEZ) or streptomycin, PAS. and a short initial period, unless there is a speci
pyrazinamidc (SPZ) are appropriate combi fic indication Nevertheless, there is sotnenations if the drugs have nm already been times a case for admitting patients to hospital
for the initial period of chemotherapy if this
used Other drugs which maybe tried are
prothionamide (or ethionamide), cycloserine, is necessary to achieve full supervision and if
thiacetazone, and the aminoglycosides other hospital beds are available. In most circums
than streptomycin, namely kanamycin or tances it is preferable to accustom the patient
caprcomycin. Previously used drugs may be to receiving chemotherapy regularly and cor
used in addition, if it is doubtful whether the rectly on an outpatient basis from the start,
strain has become resistant to them. All the organising supervision as cllicienlly as cir
drugs should be given as a single dose daily cumstances allow.
except for cycloserine and PAS which are
Whatever the level of supervision, com
pliances should be monitored by such measures
given in 2 divided doses.
as
periodic pill counts and surprise urine
;
Retreatment should be fully supervised, in
tests for isoniazid or inspection of the urine
hospital if necessary, especially in patients
for the red coloration of rifampiem.
suspected or known to have been uncoopera
tive in the past Careful bacteriological moni 7.0 Adverse Reactions
toring is essential.
The important adverse reactions to the
main antituberculosis drugs arc listed in
4.0 Cross-Resistance
Table 3.
There is no cross-resistance between iso
If clinically evident hepatitis occurs, treat
niazid, rifampicin, pyrazinamidc, streptomy
ment should be stopped until liver function
cin. ethambutol or PAS and other antitubcrtests have reverted to normal. Il is then often
culosis drugs. Cross-resistance exists between
possible to resume chemotherapy (even with
kanamycin and caprcomycin and I’ct™
the same drugs) without recurrence of the
thiacetazonc and prothionamide (or ethiona
hepatitis.
mide).
154
ANTI-TUBERCULOSIS REGIMENS OF CHEMOTHER APY
Table 2
Arthralgia can occur during pyrazinamidc women because it crosses the placenta and
administration. It is less likely to occur dur can damage the fetal eighth nerve, in patients
ing intermittent than during daily adminis with myasthenia because it is a weak neuro
tration and is usually mild and self-limited, muscular blocker, and in patients known to
be hypersensitive to the drug because of the
responding well to symptomatic treatment;
risk of a severe reaction. It should be avoid
for example, with aspirin.
ed in patients with impaired renal function
It is not often necessary to desensitize
because it is excreted unchanged by the kid
patients to antituberculosis drugs for hyper
sensitivity reactions, because alternative drugs neys and can also be nephrotoxic. Whenever
streptomycin is used it is essential cither to
are available. If it should prove necess use disposable needles (used only once) or to
ary, challenge doses of drugs should be ensure sterilisation of needles. When proper
given such that drugs which are least likely to
facilities for the sterilisation of needles are
have caused the reaction arc used first.
not available and especially because of the
If a serious reaction to rifampicin occurs, risks of transmission of AIDS or hepatitis
such as thrombocytopenic purpura, shock, virus by inadequately
sterilised needles,
haemolytic anaemia, or acute renal failure, streptomycin should be replaced by cthambuthe drug should be withdrawn immediately
tol.
and never given again. Similarly, if ethambu
tol causes retrobulbar neuritis it must be 8.5 Ethambutol
Ethambutol is contraindicated in young
withdrawn immediately and never given
again. Patients on ethambutol should always children and in any patient unable, for what
ever
reason, to report early symptoms of
be told to stop all their drugs and report
straightaway to their clinician if they experi ocular toxicity. It should be avoided in pati
ents with impaired renal function because it
ence visual symptoms.
can accumulate and cause serious ocular
8.0 Interactions. Contra-indications and
toxicity.
Special Problems
8 6 Patients with Impaired Renal Function
8 1 Isoniazid
Patients with impaired renal function can
Isoniazid interacts with phenytoin, car safely be treated with isoniazid, rifampicin,
bamazepine, and cthosuximide. so that the and pyra/inamide all of which should be given
dosages of these drugs may have to be reduc in normal dosage whatever the degree of renal
ed during its administration, particularly in failure.
slow acetylators.
8.7 Patients with Impaired Liver Function
8 2 Rifampicin
Since the main antituberculosis drugs can
Rifampicin induces hepatic microsomal be hcpatotoxic, it is important that in patients
enzymes and hence reduces the serum half- whose liver function is known or likely to be
lives and clinical efficacy of a number of impaired, liver function should be closely
drugs, including corticosteroids (the dosages monitored.
of which should be doubled during rifampicin 8.8 Pregnant Women
administration), digitoxin, coumarin anticoa
Streptomycin is the only one of the main
gulants, oral contraceptives. the orally admi
drugs which should not be given to pregnant
nistered antidiabetic sulphonylurcas and
biguanides, and dapsone, if given concurrently. women (sec paragraph 8 4).
8 9 Patients with Diabetes Mellitus
8 3. Pyrazinamidc
No modification to the chemotherapy
Pyrazinamidc is contraindicated in patients
with gout, because pyrazinoic acid, its main regimen is necessary because of diabetes.
However,
diabetes must be brought under
metabolite, inhibits the renal tubular secre
tion of uric acid leading to a rise in the control expeditiously and rigid control main
serum uric acid concentration and the risk of tained Since rifampicin is known to interact
with oral antidiabetic drugs, the do'C of the
precipitating an acute attack of gout.
latter will have to be carefully re-adjusted if
8 4 Streptomycin
chemotherapy includes rifampicin The dia
betic status of the patient should be closely
Young babies and the elderly are at inmonitored by
-----toxicity.
It ---------------------, periodic blood sugar estimation;
creased risk of streptomycin
toxicity,
'■ ’ ini such monitoring by urine examination is inadequate.
possible the drug should be avoided
i, lower dosapatients,
but
if it _ihas
to be given,
H
..
-i
.............. r. * •
*
’
Dr. D J. Girling
ges than those shown
.. .. in Table
- 2 should be
Professor P. Caulct
used. The drug is contraindicated in patients
Secretary : Dr. S.P Panira
with conditions affecting the eighth cranial
Presiilent
:
Professor
.I. A Pilheu
nerve because of its ototoxicity, in pregnant
Drug Doiagei
Daily dosage___
Drug
Adults and
children
mg,'kg
Isoniazid
Rifampicin
5
10
’
Adults
weight
<50 kg
?50 kg
<50 kg
>50 kg
<50 kg
>50 kg
Streptomycin
15-20
Pyrazinamidc
35
Ethambutol1
25 for 2
months, then 15
Thiacetazone
PAS (sodium)
Ethionamide and
Prothionamide
Kanamycin2
4lfor children)
300
15-20
Capreomycin2
Cycloserine2
15
15
1.
2.
155
ANTI-TUBERCULOSIS REGIMENS OF CHEMOTHERAPY
<50 kg
>50 kg
10-15
<5o KR
?50 kg
dose
303 mg
450 mg
600 mg
750 mg
> g
1.5 g
20g
_______ Intermittent dosage______
Adults and
Adults
children
dose
weight
mg/kg
15
15
15-20
50
3 limes a week
75
twice a week
30
3 times a week
45 twice a week
—
600-900 mg
<50 kg
>50 kg
<50 kg
>50 kg
<50 kg
>50 kg
750 mg
1 8
20g
2.5 g
30 g
3-5 g
150 mg
—
10-l5g
—
750 mg
—
I R
500 mg1 8
—
—
1 g
—
~
750 mg
—
—
1 8____________________________
It is important to calculate the dose accurately to eniurc efficacy and avoid toxicity.
Adulta only.
Table 3
Adverse Reactions to the Main Anti-tuberculosis Drugs
lioniizid
Uncommon : hepatitis, cutaneous hypersensitivity, peripheral neuropathy (preventable and treatable
with pyridoxine).
Rare: Giddiness, convulsions, optic neuritis, mental symptoms, hcamolytic anaemia, aplastic
anaemia, agranulocytosis, lupoid reactions, arthralgia, gynaccomastia.
Rifampicin
Uncommon : hepatitis, cutaneous reaction, gastrointestinal reactions, thrombocytopenic purpura;
febrile reactions (' Hu" syndrome) during intermittent or irregular administration.
Rare (during intermittent or irregular administration): shortness of breath, shock, haemolytic
anaemia, acute renal failure.
Streptomycin
Common : cutaneous hypersensitivity, giddiness, numbness, tinnitus.
Uncommon : vertigo, ataxia, deafness.
Rare : renal damage, aplastic anaemia, agranulocytosis.
Pyrazinamidc
Common : anorexia, nausea, flushing.
. , .
,
....
Uncommon : hepatitis (dose-related), vomiting, arthralgia, cutancus hypersensitivity.
Rare : sideroblastic anaemia, photosensitisation.
Ethambutol
Uncommon : retrobulbar neuritis (dose-related), arthralgia.
Rare : hepatitis cutaneous hypersensitivity, peripheral neuropathy.
Thiacetazone
Common : gastrointestinal reactions, cutaneous hypersensitivity, vertigo, conjunctivitis.
Uncommon . hepatilis, erythema mnltiforme. exfoliative dermatitis (more common in some popu
lations than in otheis). haemolytic anaemia.
Rare ; agranulocytosis
PAS
Common : gastrointestinal reactions.
Uncommon : cutaneous hypersensitivity, hepatitis, hypokalacmia.
Rare : acute renal failure, haemolytic anaemia, thrombocytopenia, cypothyroidism.
5
Ind. J. Tub., 1988, 35. 123
SHORT COURSE CHEMOTHERAPY-REWARDS & CHALLENGES*1'
M.A. Seetha*
E-
Omary : Different regimens under Short Course Chemotherapy arc being prescribed to-day with
ih hopes based on the results of clinical trials. But under field conditions many factors come in
e way of success while using the Short Course Chemotherapy. Some of these issues arc highhted.
luction
During the last four decades, remarkable
has been achieved in the chemothcratubcrculosis
biggest breaktuberculosis The
ough has been the discovery of potent
tericidal drugs like Rifampicin, Pyrazinale,'
e, INH, Streptomycin and the developit' of drug regimens to prevent drug
stance.
SVarious clinical trials in different parts of
th< world using Rifampicin and Pyrazinamide
have given very good results and many
regimens have been developed, which have
reduced the period of treatment to 6 to 9
months.
■
SToday, most doctors treat tuberculosis
patients with Rifampicin and Pyrazinamide
uwally.
Rewards with
(sec)
Short-Course
Chemotherapy
the patient to complete the treatment
in the prescribed period.
(c) Because of the short duration of
treatment, the organisational elforts
required in terms of repeat motiva
tions, defaulter action etc., are
comparatively reduced. *
(d) The cost of treatment with SCC is less
than that of treatment with standard
regimens where Streptomycin and
PAS are included.
Evcn though the rewards appear to be
promising, it is not easy to reach them be
cause the challenges arc gigantic.
Challenges in the Success of SCC
The spectacular results in terms of early
sputum conversion and no relapse were obtain
ed in clinical trials where patients arc highly
selected and every dose of medicine is almost
pushed into their mouth.
• (i) Reduction in the duration of treat-y
Hut, in the field conditions where a
ment from 12-18 months to 6-9 doctor has to treat patients irrespective of
'j
months.
their previous treatment, place of residence,
etc., the same results are difficult to obtain.
(ii) Early sputum convcrsion. (iii) No relapse, or even if it is there, it is
Some of the major reasons are:
minimal.
(i) Lack of knowledge of proper regimen.
These spectacular rewards are the results The practising doctors—whether in govern
ofclinical trials which arc similar to laboratory ment service or doing private practice, arc
conditions where most of the variables are generally not aware of the clinically proven
controlled. As a result of these rewards, the regimens and write prescriptions with com
medical profession claims great advantages
bination of drugs of their own choice. It is
like:
obvious that such combinations of drugs
without proper dosage, rhythm of intake and
(a) Early sputum conversion will have a ^duration will not give the expected results.
great impact on the epidemiological They may even harm the patients by creating
situation flnd would help in reducing
drug resistance.
the problem in the near future
(b) Reduction in the duration of treat
(n) Today, it is common
knowledge
ment will infuse greater confidence inj that the patient is the deciding factor in coni-
•Asst. Training Officer, National Tuberculosis Institute. Bangalore
••Paper presented at the 42nd National Conference on Tuberculosis and Chest Disease held in Lucknow
(Uttar Pradesh) from 2nd to Sth December, 1987.
pletion of treatment. The patient, the family,
and even friends, influence the decision
a
making process of treatment completion.
The results of SCC regimens in the 18
districts where Tuberculosis Research Centre
Under the clinical trial with SCC which
jt often is biphasic, about 49.0% in the
|y phase and 31.9% in the biweekly phase
not default even once. That is, almost
f of the patients defaulted even though
j were motivated repeatedly by doctors and
er staff members.
it be for SCC or standard regimen.
These findings show that the challenges iti
the field conditions are gigantic.
<
L (iii) Organisational efforts needed for th-j
of 222.
SSC. Tt.
The belief that because
success cf
Table 1
Cohort Analysis—SCC (7 Districts}
Regimens
No. of
Districts
2 H.R2Z,/4 H2R3
or
2 HRZ/6 TH
3
2 HRZ.’6 TH
3
2 HRZ/4 H.R3
or
2 HRZ/6TH
Treatment
Completed
(Mean) %
Cases
Admitted
Similar results have been seen in North
Arcot district of Tamil Nadu where TRC
carried out its first field study (Table 2)
(Sudarsanam 1985) Patients who made >40
collections were 43.7%, among those treated
at DTC and of those who were treated at
Peripheral Health Institutions (PHls), only
32.8% made more than 40 collections. In
this district, inputs by TRC in terms of
frequent visits to PHI, maintaining constant
supply of drugs, etc., were more than what
can be undertaken by any District Tuberculo
sis Officer (DTO). Then, in a district where
DTO is left to manage the programme, com
pletion of treatment may be the same whether
Diitribution of Case] by Number of Defaults
Type of Centre
Distribution of Patients
Treating Patient
Upto 40
DTC
49 (56.3)
PHI
311 (67.2)
With this defaulter pattern, the defaulter
lions arc not reduced, irrespective of the
Ik regimens. Table 5 shows the elTorts
ide bv doctors and the stall involved in a
38 '43.7)
- •
defaulters. (Aneja
clinical■ trial• to retrieve
152 (32.8) 1%2).
DTP
360(65.4)
190(34.6)
More than 4(,
%
0
19
7.8
17.1
I
42
4J
17.6
3
39
15.9
4
24
9.8
5
22
9.0
6
11
45
7
18
7.3
8
8
3.3
9+
19
7.7
Total
245
100.0
In an operational study conducted by NTI
tatudy the feasibility of SCC under District
faerculosis Centre (DTC) conditions, it was
fed that only 7.8% did not default. Table
fives the details (Jagota, (1987). It is seen
lhe Table that 170 (69.4%) patients have
We 1 to 5 defaults.
Table 2
SCC Field Conditions North Arcot District
Drug Collection
No.
2
d staff of PHls are least bothered, 79.5.0 of
I patients defaulted.
st;
Patients
No. of Defaults
4.0H I In the programme conditions when doctors
13.0
112
(TRC), Madras, made field trials, have not
been encouraging as shown in Table 1.
(Tubcrasculosis Research Centre,
Madras,
Personal
Communication). The treatment
completion has been of the order of 49% to
55%.
Boa
41.0
55.0
695
% S
38.0
Table 4
In an operational study of National
berculosis Institute (NTI), 90.3% defaulted
en they were on biweekly supervised
ijmen when patient himself had to come
i 88.9% patients put on unsuperviscd daily
amen defaulted-
Other"
Lost
Of
/o
49.0
3238
1
123
SHORT-COURSB CHEMOTHERAPY—REWARDS & CHALLENGES
M.A. SEETHA
124
The number of motivations at the clinic in
a month and the number of home visits arc
Table 5
.
Clinical Trial : Number of Defaulters and Total Number of Actions Taken in Each Month
!shorter duration of treatment, dcfaultc
actions, etc., arc minimised may not be true
Table 3, gives the defaulter pattern und.l,.fftrent conditions. (Aneia
(Aneja 1982).
<different
Month
No. of
Patients
Table 3
Defaulter Pattern Under Different Situations
No. of
Patients
Making
Default
Total No. of
Home Visits
Total No. of
Clinic Motivations
Proporation of Patients Making
No. of
Patients
No Default
Daily Phase
287
49.4
50.9
Biweekly Phase
182
31.9
65.6
Biweekly Supervised Regimen
282
9.7
90 3
Daily Self-Administered
242
II.I
88.9
Situation
1 or More Defa
Clinical Trial
Programme
522
20.1
Daily Phase
I
79.5
292
60 (20.5)
7'
118
288
90 (31.2)
104
214
287
95 (33.1)
145
213
IV
185
88 (47.6)
139
157
V
183
87 (47-5)
134
167
II
Operational Study
Self-Administered
■
III
Biweekly Phase
126
M.A. SEF.THA
so many that PHls do not have the means nor
the inclination to undertake the responsibilities
to see that the patients complete the treat
ment.
(iv) Adverse symptoms
It is claimed that toxicity for Rifampicin
and Pyrazinamide are not high enough to
cause worry. But adverse symptoms which
may or may not be due to the drugs can cause
concern to the patients and if treating
physicians arc not careful to attend to the
patients they are bound to default. Table 6
gives the adverse symptoms observed in an
operational study with SCC conducted by
1%) - --had
NT1. (Jagota. 1987). While 20
‘ ‘
,, (10.3°/*
adverse symptoms due to the drugs, 70 (34.4%)
had adverse symptoms due to other reasons.
I
SHORT-COURSE CHEMOTHERAPY—REWARDS & CHALLENGES
1982.) The patients with adverse symptom
were as high as 58% to 68% in daily phase o<
the treatment. If these are not
t~ perly, the results from SCC would
uld be no goo®’.
»s-.“P7
(v) The defaults due to adverse symptotr
or other reasons need defaulter action. W),
the adverse symptoms arc more, it would I
advisable to distribute drugs fortnightly, at
least in the initial stages, so that the patient
may be observed. The number of defaultactions to be taken is calculated below. While
calculating the actions to be taken, the assun
ption is made that every drug collection has/
potential of a default requiring two action'(assuming that patient does not respond let
first action) so that ■
maximum
number oh
d,*
defaulter
actions required is calculated.
Example 1: SCC
2SHR
(Daily)
Table 6
Distribution of Cases by Adverse Symptoms
1
No. of
Patients
%
Adverse Symptoms Present
I
4
I
(i) Due to Drugs
21
10 3
(li) Due to Other Reasons
70
34 4
No Adverse Symptoms
112
55.1
Total Patients
203
99.8
Table 7 shows the adverse symptoms
observed in a clinical trial with SCC (Aneja.
Table 7
Clinical Trial SCC : Adverse Symptoms
weekly Supervised)
U-1NH
Month
No. of
Patients
No.
/o
Daily Phase
I
292
169
57.9
11
288
195
67.7
Ill
287
166
57.8
Biweekly Phase
I '
IV
185
68
36.8
V
183
35
19.1
W
Relapse
Efficacy
(Clinical Trials)
Rate
. _inh TZN
11
I*—INH + 5M (Bi
PAS
82%
94%
9%
15%
84%
Is—Biphasic
INH + SM + ETMB
or
TH
96%
+ 6TH
(drugs issuct
once a month
5%
86%
Le-INH t ETMB
It is proved that the relapse rate with
SCC under clinical trials is almost nil provid
ed the patients complete the treatment in
in the
the
stipulated period. Tabic 8 gives the relapse
rate for standard drug regimen as provided io
DTP to-day (Baily 1985). The relapse rat.
tn Ra, R3, Rr, is significantly low. Thus.
relapse rate can be reduced only when the
patients complete the treatment as desired.
(vii) Cost of treatment
Cost of chemotherapy should be considered
as (1) direct cost of the drug (2) indirect com
in terms of organisational efforts. Cost benefii
analysis and cost effectiveness are also to be
b
\
4
■1’
.,
£
discordant notes as mentioned in the TRC
Report of their experiences in 18 districts. W
The report has highlighted the factors that
would give good results and these are streng
thening of PHIs, more facilities to DTO and
his team, constant supply of drugs etc., which
are very crucial and improvement of these
would also improve patient compliance with
standard drug regimens. Community involve
ment in addition to strengthening of PHls,
qualitatively and quantitatively, is the key to
the success of any chemotherapy regimen.
Acknowledgement
6%
During first two months the patient has tc j isidered in policy decisions. DTP is part
There would be 60 occasion'] social planning. Control of tuberculosis
for default requiring a minimum defaults ] inot be achieved at the cost of other
action of one daily (??)
relopmental programmes. Excess expenditl on short course Chemotherapy should not
During the 6 months when tmonthly^ at the cost of improving basic health ser
collections arc to be made. 6 defaultss cad es at the periphery? If other drugs available
occur requiring 12 actions.
the country can give almost similar results,
sp thought should be given to the chemoExample 2 -. INH + Ethambutol for I*
.rapy policy. This argument is not to decry
months (Patient collecting drugs once
SCC but only to give a proper perspective in
month)
osculation.
The maximum number of defaults could lx | Thus, the challenges are more in SCC.
18 requiring 36 defaulter actions at the most, -rf ,e success of SCC depends on the proper
tajpwledge of doctors about the drug
The need for taking defaulter actions will regimens. They should realise the importance
be more if supervised regimens are offered.
of gaining the confidence of patients by
prescribing acceptable drug regimens, repeated
Thus, the claim that fewer defaulter actions
would be needed with SCC is not true.
conic
daily.
n-dnity.
(vi) Relapse rates
No. with
Adverse Symptoms
u,,der DTF
Regimens
127
motivation, timely defaulter actions, taking
Tables
The author thanks Dr. G.V.J. Daily,
Director of the Institute for giving permission
to present the paper, and to Miss Padmalatha
Krishnan and Miss T.J. Alamelu for secretarial
assistance.
REFERENCES
Aneja, K.S. and Rupert Samuel G.E. (1982) "Organ
isational effort in a clinical trial and its retcrcnce
to applicability of short course chemotherapy in
National Tuberculosis Programme" Ind. J. Tub.
29. 19.
Baily. G V.J. and Jagota. P. (1985) “Chemotherapy
of tuberculosis", NIT Newsletter 21/3, 54.
Prabha Jagota el al (1987) "The acceptability and
cfficiacy of two regimens of Short Course
Chemotherapy under conditions of an urban
tuberculosis programme" To be Published.
Sudarsanani. N.M. (1985) "Short Course Chemother
apy under District Tuberculosis Programme"—
Paper presented at the 39th National Conference
on Tuberculosis and Chest Disease at Cuttack
(Orissa),
Tuberculosis Research Centre. Madras; Personal
Communication.
FIELD TRIAL OF SHORT TERM INTERMITTENT CHEMOTHERAPY
Ind. J. Tub., 1988, 35, 176
The present study was taken up in Febru
ary, 1982 at the Mahatma Gandhi Institute of
Medical Sciences, Sewagram, Wardha to
assess the efficacy of two short term fully
intermittent regimens under field conditions.
The efficacy of two biweekly regimens, one
suitable for urban and the other for rural con
ditions, in previously untreated pulmonary
tuberculosis patients is reported, based on
interim results upto 30th June, 1986.
FIELD TRIAL OF SHORT TERM INTERMITTENT CHEMOTHERAPY OF
PATIENTS WITH PULMONARY TUBERCULOSIS IN WARDHA DISTRICT
S. Na VAR,1 P., Narangs N.K. Tyagi,3 U. Jajco,4
V.R. Dhage,5 and M. Bharamde®
Summary : Short course intermittent chemotherapy regimens for pulmonary tuberculosis were given
a field trial from February 1982 to lune 1986 in district Wardha, Maharashtra The symptomatics
were picked up by door to door survey and newly detected cases who were culture positive were put
on treatment. The regimens for the urban patients were 2S.H_.R2Z2/4S2H2 (NUI) and in half of the
randomly selected patients the regimen was extended by 2S>H2 (NU2). For the rural population,
the regimen was 2H2R2Z2/4H,R2 (NRI) followed by further 2H2R2 (NR2) in the half of the patients
selected randomly.
Under this field trial a total of 112 patients received the regimen NUI. The percentage of
patients who become sputum negative at 15 days was 44.6%, at 60 days 54.5% anil at The entTofTreatmenrre. 180 days, 69.6%. The extension of freatmenl by two months‘tNU2) in 6! subjects did not
improve the efficacy but one bacteriological failure became negative.
In the regimen NRI. 217 patients were given treatment and at 15 days the sputum negativity was
57.9%, at 60 days. 6T5% ™d at the end of treatment, i.e. 180 days. 16.0f. In 140 patients the regimen
NRI was extended by two months (NR2) but there was no improvement in the negativity rate.
The efficacy of the regimens, when calculated in patients who had consumed 80%, or more than
80% doses'by lhe end of the treatment was 94.8% in NUI and 97.5% in NRI. The defaulter rate in
regimen NUI was 26 8% and in NRI 22.1%. In both the regimens it was maximum In the first two
months.
--------- - 1
i ihji*
The relapse rates were 0%, 0.27%, 0.97% and 3.19% in regimens NUI. NU2, NRI and NR2
respectively.
Introduction
Chemotherapy has revolutionised the
treatment of tuberculosis. Short term che
motherapy has given new hope of tuberculosis
control A number of controlled clinical
trials all-over the world have proved beyond
doubt that the bactericidal drugs in various
combinations offer effective treatment of tu
berculosis in a much shorter time. Further, in
the mid-sixties, the Chemotherapy Centre
at Madras showed that it was the peak and
not the sustained level of drugs in the patients’
blood which was more important This led
to the concept of intermittent therapy with
----- The results
.-----higher doses of drugs.
were satis
factory. Both in vitro and in vivo experi
mental evidence provided by Grumbach, et al
1964, Dickson and Mitchison 1966a, 1966b,
Grumbach, et al 1967, Mitchison 1970, has
encouraged the use of intermittent therapy in
the treatment of this disease.
As shown by some studies (Fox 1979,
Sivaraman 1983), intermittent chemotherapy
has the advantage of not only lowering the
1.
2.
3.
4.
5.
6.
cost of drugs but also decreasing the toxicity
and side-effects of the drugs, besides encoura
ging the patients to complete the treatment.
While most of the short course regimens in
the past have been used in controlled clinical
trials with a daily intensive phase followed by
an intermittent continuation phase, (Hong
kong Chest Services,BM RC 1978, 1979; East
African/BMRC 1972, 1974, 1978, 1981. Tripathi 1979, 1981, Zierski, et al 1980, 1981);
some of these studies have also been opera
tional. (Amstasatu 1977. 1982: Hongkong
Chest Service/BMRC 1978. 1979, 1981: Eule,
et al 1982, Krishnaswami, et al 1982). Controlled clinical trials with intermittent regimens throughout have also proved effective
(Gonsalves, et al 1982, Pacheo. et al 1982,
Iturbe, et al 1982, Farga, et al 1982) but their
applicability in field conditions remain to be
tested It has been observed that the success
rate of any chemotherapy under field condi
tions falls much below that observed under
controlled clinical trials. Therefore, field
trials of intermittent chemotherapy in rural
and urban population were considered neces
sary.
Director, M.G. Institute of Medical Sciences.
Professor & Head. Deptt. of Microbiology.
Reader in Statistics & Demography.
Asso. Prof. Medicine.
Research Associate.
Statistician.
Material and Methods
The symptomatics identified during door
to door survey were asked to provide samples
of sputum, one spot and other overnight
collection. Whenever spot sample was not
available, two overnight samples were collec
ted.
Sputum specimens were collected in wide
mouth sterile containers and brought to the
Microbiology Laboratory of Mahatma Gandhi
In.titute of Medical Sciences within 5-8 hours.
The samples were subjected to direct micros
copy by Ziehl Neelson's method and cultured
on Lowenstein Jenson medium. For analysis,
symptomatics positive by culture only were
considered as bacillary positive cases And
those culture negative at one examination but
positive subsequently were categorised as
positive.
P
i
i ■
!
(
•J
4
i
a
<’1
ij
;
X
;i
5
M.G. Institute of Medical Sciences, Sewagram.
Reprint Request : Dr. P. Narang, Professor & Head, Deptt. of Microbiology, M.G.I.M S. Scvagram,
Dist: Wardha.
It a as decided to give 6 months of bi
weekly therapy
In the urban cases, for the
first two months, four drugs i e , Streptomy
cin. Isoniazid. Rifampicin and Pyrazinamidc
were given and for the next four months i.e.
maintenance phase, only two drugs namely
Streptomycm and Isoniazid were given (NUI).
At the time of case detection, half of the
patients were randomly allocated forextension
of the two-drug maintenance phase by ananother two months; this group was labelled
NU2. However, till the end of 6 months
patients on both the regimens have been
analysed together.
Similarly, all rural cases were given three
drugs i c . Isoniazid. Rifampicin and Pyrazinamide for two months and then only Rifampicin and Isoniazid for another four months
(X'RD. in the case of rural patients also,
(NRI).
half were randomly allocated, at the time of
case detection, to extended therapy for another two months with two drugs (NR2> Till
6 months, patients in regimens NRI and NR2
also have been analysed together. All the
patients were newly detected cases who gave
no history of having taken antitubercular
drugs in the past. All the patients were then
’objected to a thorough clinical examination
including chest skiagram.
>
i
7^
177
The therapy given is summarised below :
Regimen
1.
Rhythm
Duration No of doses
New Urban (NU)
NU1: 2S2H2R2Z2/4S2H2 Biweekly 6 months
57 (19 |-38)
NU2 : 2S2H2R2Za/4S2H2/2S2H2l> 8 months
76 (19 + 57)
2.
New Rural (NR)
NR I : 2H2RaZ2/4H2R2
,,
6 months
57(19 I 38)
NR2 : 2H2R2Z2/4H2R2/2H2R2 „
8 months
76 (19+57)
Dosage
As assessment of weight under
field
conditions was difficult, the same doses were
maintained for all the patients in all the regi
mens.
Streptomycin (S)
Rifampicin (R)
Isoniazid
(H)
Pyrazinamidc (Z)
0.75 gm
600 mg
600 mg
3.0 gm
In the urban areas patients were called to
specified centres and the drugs were adminis
tered to them under direct supervision of the
medical olTicer.
In rural areas the patients were supplied
their quota of drugs every month at their door
step and how to take the doses was fully
explained. Their therapy was, thus, domicili
ary and self administered. In these cases,
surveillance of drug compliance was done by :
(1) counting die left over pills;
(2) checking the colour of the patient’s
urine for Rifampicin intake; and
(3) checking the excretion of INH
metabolites in the patient’s urine.
Checking under 2) and 3) was done
by surprise on some of the patients.
During treatment, sputum samples were
collected at I st and 2nd months in the inten
sive phase in which four drugs were adminis
tered to the urban and three drugs to the
rural patients and after every month in the
continuation phase, in which only two drugs
were administered. Sputum collection after
I 5 days of therapy was also done but was
begun a little later in the study.
A patient was considered cured if he,'she
FIELD TRIAL OF SHORT TERM INTERMITTENT CHEMOTHERAPY
179
S. NAYAR, et al.
178
Table 2
At the end of the treatment at 180 days
i.e., after 4 months of maintenance phase
(SjHs), sputum was cultured in only 82
patients, 30 having dropped out. Seventy
After completion of the therapy, patients
were kept under surveillance for one year, and eight patients (69.6%) were found to be cul
sputum was collected at the end of 1st, 4th, ture negative and 4 (3.6%) were still positive.
The overall efficacy of the NUI regimen under
Sth and 12th months to detect any relapses.
field conditions was, therefore, 69 6% with
Similarly, patients were monitored radio-* 3.6% treatment failures and 26 8% cases lost.
logically every two months during the treat
Analysis of the prescribed doses taken
ment and at 6 months and 12 months in the
showed that 77 (68.75%) cases took 80 per
follow up phase.
cent or more of the total doses (Table 3). At
the end of the intensive phase, i.e., at 60 days,
Patients becoming culture posifive one
month after stopping the treatment were con sputum negativity was 80.3% and at the end
sidered as relapsed cases. Those who never of treatment it was 94.81 per cent among
became negative or those who became positive them.
within one month after treatment were consi
There were 9 cases who had taken 50-79
dered bacteriological failures.
per cent of the total doses and only 4 were
available for analysis at 180 days. All the ^4
Results
Of the 25
26
patients were culture negative. Cf
patients who took less than 50 per cent doses
A total of 112 newly detected patients only one was analysed at 180 days and was
were put on regimen NUI, i.e., 2S2H!R2ZI/ found to be negative.
4SjH2. However, at the end of 180 days only
Two hundred and seventy one patients were
82 patients could be analysed as three patients
died and 27 were lost to treatment (Table 1)
putt on regimen NRI i.e, , 2H.
e - R.Z
- -= 4H2 R;
(Table 2a). At the end of the treatment
total
of
211
patients
could
be
analysed,
52
''
.................................
The culture negativity of sputum at diffe at,.
lost to. treatment
and 8 died. By the end
.
rent check points in patients put on regimen were__
NUI is shown in Tabic 2. At 15 days, i.e., of
— 15 days 157 (57.9%) cases were found to
'
.
. The figures at
after 4 doses, 50 (44.6%) cases were found to have culture negative
sputum,
(63.5"i,) and at 180 days
culture
25 were still positive but
but 60 days were 172 (63.5",.)
;be
____
__ negative,7-5
.in —
.
...
..
206
C
7
6.o%).
The
overall
cllicacy of
29 the sample could not be examined and 8 were 206 (76.0%). TI.----patients had dropped out of the regimen. At this regimen under field conditions was there’ ... 76%
.........
the end of the intensive phase, i.e , at 60 days, fore,
76.0 r
per
cent■-. Five cases (1.9%) were
61 (54.5%) cases were found to be culture babacteriological
'
1 failures and 60 cases (27.1%
negative, and 16 (14.3%) were still positive.
wi;ere lost to treatment.
became culture negative at the end of the
treatment.
Table 1
Not examined
Category/
Check point
No. eligible
for intake
No. dropped
out or died
No. assessed
at six months
NUI
112
(100.0)
30
(26.8)
82
(73.2)
NRI
271
(100.0)
60
(22.1)
21 I
(77.2)
Regimen/
Group
No. eligible
at intake
No. eligible
at six months
NU2 ’
61
(100 0)
41
(67.2)
(67 2)
NR2 •
140
(100 0)
108
(77.1)
(77.1)
(%)
(%)
(%)
No. assessed
at eight
months
41
108
• These cases were randomly allocated at the beginning of the treatment to receive the extended therapy
of two months from NUI and NRI. Those available at 180 days were continued on treatment.
missed
out
Total
Cui. + vc
Cui. - vc
Total
8
25
(22.3)
50
(44.6)
75
(67.0)
(7.1)
29
(25.9)
37
(33.0)
—at end of 60
days (%)
8+15
(20.5)
12
(10.7)
35
16
(31.2)
(14.3)
61
(51.5)
77
(68.8)
-at end of 180
days (%)
8+15+7
(26.8)
.30
(26.8)
4
(3.6)
78
(69.t,)
82
(73.2)
NRI ;
271 Cases in all
—at end of 15
days(%)
6
(2.2)
(26.6)
78
(28 8)
36
(13.3)
157
(57.9)
193
(71.2)
—at end of 60
days (%)
6 I 27
(12.2)
(15.1)
74
(27.3)
25
(9.2)
172
(63.5)
197
(72.7)
60
(22.1)
5
(1.9)
206
(76.0)
211
(77.9)
—at end of 180
6 ' 27
dayi(%)
72
41
27
(22.1)
Table 3
Results of treatment according to regimen and regularity of taking prescribed doses at two
completion points
Regimen/
Point
Total No.
assessed
? 80% doses
<80% doses
Number
assessed
Cui.
Cui. [ ve
Number
assessed
Cui.
Cui.
8
(72 73)
3
(27.27)
NUI (N=112)
—at (0 days
77
66
53
(80.30)
13
(19.70)
11
- at 180 days
82
77
73
(94.81)
4
5
("..)
NRI(N 271)
—at 60 days
(".,)
(%)
Examined
dropped
out
NU1 :
112 Cases in all
—at end of 15
days (%)
<%)
Distribution of cases according to drug regimen at the time of intake inot study
Regimen/
Croup
Culture status of NUI and NRI cases at different check points during six months period of treatment
—at 180 days
("..)
197
211
169
197
(5.19)
147
2’’
(86.98)
(1+02)
192
(97.46)
5
(2.54)
Dosewise analysis revealed that 197
(72.69%)patients had taken 80 per cent or
| more drugs (Table 2b). The bacteriological
^negativity of these patients at the end of 15
• Ud) s
ft^days
was 82.32 per cent, at 60 days it was
?i86
- 9X
-3 per cent and at 180 days it was 97.46
Per cent. The bacteriological failures were
I 2.54I per cent.
I here were 30 patients who had taken
50-79 per cent of the treatmen! and only 12
ve
(100.0)
28
1-1
25
(89.29)
3
(10.71)
14
(100,0)
were available for analysis at ISO days. All
the 12 were found to be culture negative. In
44 patients who had taken less than 50 per
cent doses assessment at 180 days was done in
only 2 patients and they were both negative.
In 61 urban cases, maintenance phase was
to be extended by another 2 months bv ran
dom allocation (NU2: Table 1). At ISO days
37 (60.7%) sputum negative, 2 (3.3%) sputum
positive, and 2 (3.3%) sputum not examined
B-
FIEED TRIAL OF SHORT TERM INTERMITTENT CHEMOTHERAPY
S. NAYAR, et al.
180
and these included 8 (3.0%) deaths. There
were no defaulters amongst the patients whose
treatment was extended beyond 180 days.
i.e. 41 (67.2%) cases only were available for
NU2 treatment. At the end of 8 months i.e.,
at 240 days 40 (65.6%) patients were sputum
negative and one was still positive (1.6%)
Out of a total of 112 patients put on urban
In 140 patients out of 271 placed on rural regimen NUl, 46(41.1%) showed mild side
regimen, the maintenance phase was to be efiects. In rural regimen NRI, out of 271
extended by another 2 months (NR2). Out patients. 94(34.6%) had side effects. 1 he side
of these. 108 (77.1%) cases were available for effects in the urban regimens were apparently
NR2 at 180 days. The culture status of these higher as compared to the rural regimens but
patients at 180 days was 100 (71.4%) negative, the difference was not statistically significant.
2 (1 4%) positive and 6 (4.3%) sputum not
The side effects observed in majority of
examined. At 240 days, it was 106 (75.7 %)
71’4%)' “bacteriological the patients on urban regimen were pertaining
negative, and 2 ('..'??
•* the gastro-intestinal tract (94",, of the total
.. —. ’. 1 --------------1 ncr'
Ialluresside effects). Four per
cent had central
symptoms and 2 per cent had
All the patients who were negative at the vous system s,
... In the rural icgimens, out
end of their treatment were followed up for dermal problems,
who showed side effects, 81
relapses for one year. Out of the 78 patients of 94 patients wl
(86.11%)
had
gastro-intestinal symptoms,
who were negative at the end of the regimen
NUl (Table 2), 41 were given extended treat 8(8.5%) had central nervous systems symptoms
ment for 2 months (NU2 Table 1), and the and 2 (2.17%) had symptoms concerning
remaining 37 were left for follow up the skeletal system.
(Table 4). Simi/arly, out of the 206
In two cases the regimens had to be dis
patient on NRI. 108 were allocated to continued because of toxicity, one was a case
NR2 and 98 were followed up (Table 4).
of 'flu' syndrome in regimen NUl and the
other of generalised skin eruptions developing
Out of the 37 patients for follow up at the two days after the consumption of drugs in
end of 6 months treatment in NUl, only 36 regimen NRI.
could be followed up and there was no relapse
amongst them (Table 4). Out of the 41 sub Discussion
jects for follow up in NU2, 36 were contacted
The present study was undertaken to deter
and one had relapsed. In NRI, 97 cases out
mine the efficacy under field conditions of two
of 98 were followed up and there was one
totally intermittent regimens which would
relapse amongst them. In NR2, out of the
108 only 96 patients could be followed up cost less and yet be efficacious. The urban
regimens (NUl and NU2) were supervised
and 3 cases of relapse were detected.
and included streptomycin injections in the
In the urbane regimen ^n/
NUl,
out1 .of
the 112
\
I 4*
. 1
patients assessed,
23 (20.5%)
defaulted
within
--wz
—
rr
.
...___ . zT-ut.
Another
60 days
of .treatment
(Table 2)
Another
7(6.3%) defaulted during the period 60 to 180
days. The total defaulters in this regimen
were 30 (26.8%) which is inclusive of three
patients (2.7%) who died during the treatment. In the rural regimen NRI, 60 (22.1 „)
out of 271 patients put on treatment defaulted
zmzx
paillllCJ *• J
intensive as well as in the maintenance phase,
r.:.'—.,.:.:.! was not given to these patients in
Rifampicin
the
maintenance phase. The rural regimens
the maintcn
(NRI and NR2) were self-administered domi
ciliary regimens where the drugs were supplied
to the patients at their door steps The regi
mens were non-injectable and included rifam
picin instead of streptomycin in the mainte
nance phase.
Table 4
Regimenwiie distribution of relapsed cases during a period of one year
Regimens
Status of cases
NR.
NUj
NU.
NR]
Patients eligible to
be followed
37
41
98
Number followed-up
36
(97.3)
36
(87.8)
97
(99.0)
96
(88.9)
Number relapsed
0
(0.0)
(0.3)
I
(10)
3
(3.1)
(%)
(%)
108
181
even though they arc intermittent
intermi ttent and biweebiwee
kly. The importance of this in the reduction
of
• r infectivity
'—c—:■
in •the
u- community is obvious.
-»•••:—As the idea of assessment of efficacy at 15
days was a later addition to the protocol of
the study, in many cases the sputum was not
collected at 15 days and hence the fieldellicacyatlSdays in both the regimensis low
(44.6 and 57.9 per cent in NUl and NRI
respectively).
A good regimen is that which makes the
sputum negative at an early stage so as to
minimise the load of infectivity in the com_______
munity. Mitchison (1979) stated
that_ culture
early
negativity at 2 months is an ci;
’;- index of
~e
sterilising activity of a regimen. In controlleda
clinical trials, many of the daily regimens
have achieved mote than 90 per cent culture
negativity by the end of the second month
(Hongkong Chest Service, BMRC 1978, Singapoie Tuberculosis Service/BMRC 1979, 1981,
In the same group of patients the culture
Mehrotra 1981). Under field conditions also
some of the studies have shown over 90 per negativity of the sputum at 60 days and 180 ’
cent sputum negativity at 2 months. Gonsal days in regimen NUl was 80.3 and 94.8 per
ves et al 1982, Iturbe et al 1982, and Farga cent respectively. The figures for NRI were#
et al 1982, studied the regimen 2RHSZ/- better (86.98 and 97 46 per cent respectively#
4R2H2Z2 for 6 months and the sputum nega The bacteriological failure were 5.2 per cent
tivity at 2 months was 91.0, 94 5 and 97.0 in NUl and 2.5 per cent in NRI. These figures
per cent respectively. In these regimens, show that if the drugs arc taken regularly then
however, two months’ daily intensive phase the regimens are highly effective- The regimen
was followed by intermittent phase with three NRI which had rifampicin in the continua
drugs biweekly. The present study is a field tion phase was better though the difference is
trial and differs from the above studies in not statistically significant. Also, the addi
drug combination and frequency of drug tion of streptomycin to the regimen in the
administration. Under field conditions, the intensive phase has not yielded any additional
_ . N UI at 60 days
.
eflicacy of the regimen
was benefit. However, the follow up study of
54.5 per cent and that
t‘ of NRI was 63.5
' 7 per these patients has shown that the relapse rate
cent. This efficacy can be considered fairly was much lower in patients on streptomycin
good considering that the patients had taken regimen as compared to those on rifampicin
only 19 doses in 2 months The success rate (Table 4). The advantages of both inclusion
at the end of 180 days was 69.6 per cent in and exclusion of streptomycin from the
NUl and 76 0 per cent in NRI. In the past, Routine:
administration of antitubercular
it has been experienced that in the developing drug
■'— therapy therefore need to be studied
countries, the conventional 12 months regi further.
mens achieved much less than 60 per cent
In both regimens the extension of the
cure rate under programme conditions. Re
gimens with cure rates of 69.6"^ and 76% 6 months by additional 2 months in 61 patients
in
NU2
aud 140 patients in NR2 showed no
can be considered as attractive and acceptable
improvement either in the bacteriological
for our country.
negativity or the relapse rate, though in the
The lower eflicacy of the urban regime^ regimen NU1. I out of the 2 bacteriological
was observed to be the result of more lost failures did become sputum negative after
patients (26.8%) and the bacteriological fai 2 months of additional drug therapy. It
lures (3.6%). The same figures for NRI were seems that, even under field conditions, for
22.1 and 1.9 per cent. The main reason for biweekly regimens like NUl and NRI. a dura
this was that besides being an injectable regi tion of six months is quite sullicicnt and the
men, in the urban regimen the patients were therapy needs be extended only for treatment
asked to come and take the drugs at a speci failures. This would reduce both the dura
fied place and many of them defaulted to tion and expenditure on the drugs.
avoid the stigma of going to the Centre.‘*lJsc
Defaulter
in both regimens
were maximum
of paramedical personnel for supplying the
jxur^"-~
"
drugs to the patients at their homes may yield within the first two months, Those patients
better results than calling the patients for who were able to tolerate the drugs in the
intensive phase had very little problem during
drugs to the tuberculosis centres.
the continuation phase and the drug that was
In this study, an attempt was made to not given in the continuation phase in any of
assess the bacteriological negativity of the the regimens was pyrazinamide. Probably,
patients at 1 5 days i.c.. after giving 4 doses the high dose of 3 grams was difficult to to
only. In patients who had taken 80% or lerate and the patient sulfered from gastritis,
more than 80 per cent doses, the bacteriologi nausea and vomiting.
cal negativity at 15 days was 67.2 per cent in
It is concluded that the present totally
NUl and 82.3 per cent in NRI. This indica
tes a good sterilising activity of these regimens intermittent biweekly regimens with good
182
S. NAYAR, et al.
sterilising property, low cost and more than
60 per cent effectiveness could be used under
field conditions to bring about a rapid reduc
tion in the infectivity poo).
Acknowledgement
The authors are grateful to the Indian
Council of Medical Research for financing the
project, and to the Dean, Dr. K.S. Sachdeva,
Mahatama Gandhi Institute of Medical Scien
ces, Sewagram, Wardha, for his support. The
authors are also thankful to Shri A.K. Suryawanshi, social worker and other staff in the
project for their sincere and dedicated work.
REFERENCES
Anastasatu, C., Results of a study of twice weekly
regimens for 9 months in Roumania, In Fox, W.
(Editor), The modern management and therapy of
pulmonary tuberculosis, Table 3, Proc. Roy Soc.
Med., 1977, 70.4.
Anastasatu, C., Bercea, O , Corlan, E , Pilot study of
short course (3-f-3) intermittent chemotherapy in
previously untreated, smear positive tuberculosis.
Paper presented at XXVth World Conf. IUAT,
Buenos Aires, 1982.
Dickenson, J.M., Mitchison, D A., In vitro studies
on the choice of drugs for intermittent chemo
therapy of Tuberculosis, Tubercle, 1966a, 47, 370.
Dickenson, J.M., Mitchison, D.A., Short term inter
mittent chemotherapy of experimental tuber
culosis in the guinea pigs, Tubercle, 1966b, 47,
381,
East African/British Medical Research Council,
Controlled clinical trial of short course (6 month)
regimens of chemotherapy for treatment of
pulmonary tuberculosis, Lancet, 1972, I, 1079.
East African/British Medical Rcsercb Council, Con
trolled clinical trial of four short course (6 month)
regimens of chemotherapy for treatment of
pulmonary tuberculosis. Third Report, Lancet,
1974, 11, 237.
East African/British Medical Research Council,
Controlled clinical trial of five short course
(4 month) chemotherapy regimens in pulmonary
tuberculosis, First report of 4tb study, Lancet,
1978, II, 334.
East African/British Medical Research Council,
Controlled clinical trial of five short course
(4 month) chemotherapy regimen, in pulmonary
tuberculosis. Second report of 4th study, Amer.
Rev. Resp. Dis , 1981,123, 165,
Eule, H., Beck, H., Evers, H , Fischer, P., Merkel, S.,
Reech, R., Thomas, E. Weinccks, W. Short
course daily and intermittent chemotherapy
with four drugs in newly detected bacillary
pulmonary tuberculosis. Proc. 12th Int. Congr.
Chemothcr., Florence, 1982, Vol.11. 992,
Farga, V., Mecndoza, F., ct al. Short course chemo
therapy. Two controlled operational trials in
Chile including the study of an initial daily phase
of one month and an intermittent phase of six
months and a regimen with and without pyrazinamide in the second phase. Paper presented at
XXVth World Conf., IUAT. Buenos Aires, 1982.
Fox W., Chemotherapy of pulmonary tuberculosis,
A review, Chest, 1979, 76. supple, 785.
Gonsalves, A.L., Magalhaes. A., et al Short course
chemotherapy (6 months), entirely ambulatory
and supervised, of new cases of pulmonary tuber-
culoiis with aensitive bacilli io adulta. Paper
presented at XXVth World Conf. IUAT, Buenos
Aires, 1982.
Grumbach, F., Canetti, G., Grosset J. Further
experiments on Jong term chemotherapy of
advanced murine tuberculosis, with emphasis on
intermittent regimen. Tubercle, 1964, 45. 125.
Grumbach, F„ Canetti, O., Grosser, J , Liz in, M. Late
remits of long term intermittent chemotherapy of
advanced murine tuberculosis. Limits of munue
model, Tubercle, 1967, 48, 11.
Hong Kong Chest Service, British Medical Research
Council, Controlled trial of 6 months and 8
months regimens in the treatment of plmonary
tuberculosis. Fust report. Amer. Rev. Resp. Dis.,
1978, 118, 219.
Hong Kong Chest Service, British Medical Research
Council, Controlled trial of 6 months and 8
months in the treatment of pulmonary tuberculo
sis. The icsult up to 24 months. Tubercle. 1979,
60, 201.
Hong Kong Chest Service, British Medical Research
Council, Controlled trial of four thrice-weekly
regimes and a daily regimen all given for 6
l”0!1?!15 f°r pu*'nonary tuberculosis, Lancet 1981,
llurbe, P., Morales, H.S , Paris, R. Result of a pro
gramme of short course treatment applied in the
routine health services of the country. Paper
presented at XXVth World Conf. IUAT, Buenos
Aires, 1982.
Krishnaswami, K.V., et al Intermittent short course
chemotherapy of pulmonary tuberculosis. Ind. J.
Tub., 1982, XXIX, 1 40.
Mehrotra, M.L., Gautam, K.D., Chaubc, C.K. Agra
study on short course chemotherapy in pulmonary
tuberculosis. Am. Rev. Resp. Dis., 1981, 124, 239.
Mitchison, D.A. Bacteriological mechanisms in
recent controlled chemotherapy studies. Bull, of
IUAT, 1970, 43, 322.
Michison, D.A. Basic mechanism of chemotherapy,
Chest, 1979, 76, 771.
Pacheco, C., Ramos, J„ Herrera, M.,Short course
treatment of tuberculosis, paper presented at
XXVth World Conf, IUAT, Buenos Aires. 1982.
Singapore Tuberculosis Service BMRC, Clinical trial
of 6 months' regimens of chemotherapy for
pulmonary tuberculosis. Am. Rev, Resp. Dis.,
1979,114, 579.
Singapore Tuberculosis Service BMRC, Clinical trial
of six month and four month regimens of chemo
therapy in the treatment of pulmonary tuber
culosis. the result upto 30 months Tubercle,
1981, 62, 95.
Sivaraman, V. Cost consideration in short course
chemotherapy, Ind. J. Tub , 1983, XXX, 4.
Tripathy, S.P. Madras study of short course chemo
therapy in pulmonary tuberculosis, Bull. Jnl. Un.
Tuberc., 1979. 54, 28.
Tripathy. S P. Bacteriological relapse rates in
smear and culture positive disease, very highly
elfectivc seven to nine month regimens, Brit J.
Dis. Chest. 1981. 75, 331.
Zicrski. M„ Bek, E., Long, M.W . Snider, D E.. Jr.
Short course (6-monlh) cooperative tuberculosis
study in Poland. Result IS months after compktiem of treatment, Amer. Rev. Resp Dis , 1980,
I
>
*
K-
Zierski. M., Bek. E., Long M.W., Snider. D E„ Jr.
Short course (6-month) co-operative tuberculosis
study in Poland. Result up to 30 months after
completion of treatment, Amer. Rev. Resp. Dis..
1981, 124.
£
Ind. J. Tub., 1988, 35,188
Table 1
LONG TERM FOLLOW UP AFTER STANDARD CHEMOTHERAPY
OF PATIENTS WITH PULMONARY TUBERCULOSIS
Reactivation in relation to host factors
V.P. Gopinaihan*, R. jayaswal**, K.J. Sheth*** AND S.S. GANGULY****
Factor
Summary: Two hundred ex-service personnel, presently in the age group 20-61 years, fo lowed up
for a total of 2470 person years, were analysed after they were given sundard antituberculosis
therapy 3 SHP/E and thereafter S2 Ha for periods varying from 6-24 months to ascertain the effect of
the factors, viz. age, smear/culture acid fast bacilli positivity, initial radiological extent, radiological
sequelae and duration of therapy in the reactivation of the disease.
The analysis revealed that eleven patients exhibited features of reactivation of the disease during the
follow-up. Out of the factors considered in this study, reactivation was found more common in those
who did not comply with regular and continued therapy for the recommended petiod
Introduction
Historically, tuberculosis
has been a
disease prone to relapse even after long
periods of apparent inactivity (Edsall and
Collins, 1973). Hence, long term follow-up
of patients with inactive disease is recom
mended. particularly in developing countries
where a fair number of patients do not
comply with the antituberculosis regimen in
the optimum dose and rhythm for the pres
cribed period (Philips, 1964; Grzybowski
et al. 1966; Pamra ct al. 1974; Nakielna et
al, 1975). Recognition of reactivation of
the disease in these cases is important as
they contributed about one third of all
active cases at a time and it forms a major
part of the reservoir of infection (Grzy
bowski et al, 1966). While
developing
countries contribute to three fourths of these
cases, reports of such long term follow-up
are scanty in the literature, for various social
and economic factors (Pamra et al, 1974;
1976; Chakravorty and
Gothi,
1976;
Tripathi, 1981; Crofton and Douglas. 1983).
Hence, a retrospective analysis of these
patients treated earlier with standard thera
peutic regimen and reporting to a teaching
service hospital (for assessment of disabi
lity for pensionary readjustment)
was
carried out to establish the relationship, if
any, between their reactivation of the disease
and associated factors.
Material and Methods
Ex-service personnel who suffered from
pulmonary tuberculosis (PT) while in service
and were treated as inpatients (initially in
all cases) with standard
antituberculosis
regimen and later reported for assessment of
medical disability formed the material for the
present study.
Those reporting regularly for follow-up
were subjected to clinical, radiological and
bacteriological evaluation (at least three
early morning sputum samples after saline
mouth wash) for reactivation of the disease,
if any. Patients with non-homogeneous,
static fibrotic radiological lesions covering,
in all, not more than one fifth of two lungs
put together were declared to have insigni
ficant radiological sequelae (Table 1).
Diagnosis was suggested in ‘smear cum
culture negative group' by features of tuber
culous toxaemia duly supported by softer and
increasing lung shadows (cavitary, non-cavitary, miliary or non-homogeneous) persisting
even after exposure to non-antitubercular
bactericidal antibiotics. Radiological extent
was decided by the criteria
devised
by
Tuberculosis
Association
of
India.
They were treated with Inj. Streptomycin
(SM) 0.75 — 1.0g IM, INH 300 mg single dose
and PAS 6-7.5g twice daily (or ethionamide
750 mg—1000 mg in two doses in patients
not tolerating PAS) all daily for 3 months
followed by twice weekly SM in the same
dosage as above and INH 14 mg/kg body
weight for periods ranging upto 15-21 months
(total 18 24 months). Those given alternate
regimes in different
combinations and
rhythms in 1950s or earlier (when drugs
were not available) and those infected with
AFB resistant to drugs as above were exclu
ded from the present analysis.
• Reader in Medicine
•• Professor and Head of the Department of Tuberculosis and Chest Diseases.
Formerly, Professor of Medicine.
••• Lecturer in Statistics.
Department of Medicine, Tuberculosis & Chest Diseases Armed Forces Medical College, Pune
Correspondence : Colonel R Jayaswal, Military Hospital (Cardio-lhoracic Centre), Golibar Maidan,
Pune—411 040.
189
Long term follow up after standard chemotherapy
1.
No. of
eases
Reacti
vation
%
Signifi
cance
RR"
59
141
5
6
8 47
4 26
P> 0 05
1.99
66
8
3
5.97
4.54
P> 0 05
1.31
121
6
4.9S
5
6.33
P> 0.05
0.78
79
159
11
II
6.92
44
156
6
13 64
3.20
P< 0.05
4 20
Age
ia) Above 45 yrs
(b) Below 45 yrs
2.
Smcar/Culturc
AFB Positivity
(a) Positive
(b) Negative
3.
Radiological Extent
(a)
(b)
4.
Moderate to
Far Advanced
Minimal
Radiological Sequelae
(a) Significant
(b) Insignificant
5.
Duration of Therapy
(a) <12 months
(b) >■ 12 months
Note
134
5
Moderate to Far Advanced eases include cavitary lesions.
•RR
Relative Risk
Two hundred and seventy one patients,
in the age group 20-61 years, who reported
to a teaching service hospital in Pune for
assessment of medical disability during the
period from December 1983 to June 86 were
analysed. Seventy one patients were ex
cluded for want of proper medical data and
or details of therapy administered at the time
of the acute illness.
Results
Out of 200 patients thus evaluated, majo
rity were in the younger age group. 1 leven
patients (5._y ,?) showed features of reactiva
tion. The relative risk (RR) for reactiva
tion, among those more than 45 years of age.
is about twice as compared to the younger
age group. When analysed in terms of
sputum Al B positivity, RR for reactivation
was found to be 131. T here was no cor
relation between the initial
radiological
extent and the chances of reactivation (RR—
0.78). It was interesting to note that none
of the patients having insignificant radiologi
cal sequelae at the time of completion of
therapy exhibited reactivation during the
followup thereafter (Table 1).
Duration of therapy related to RR
Only 156 patients (78%) completed the
recommended regime The same could not
be ensured in the remaining group who had
to be relcascd/invalidcd out of service for
various service factors. The observed RR in
those who did not complete therapy (mini
mum of 12 months' drug regimen) was statisti
cally significant when compared to the re
maining group (P < 0 05).
The reactivation rate dropped down as
the duration of follow-up increased. There
was only one case out of 39 patients when
they were followed up for more than 15
years (T able 2).
Tabic 2
Reactivation in Relation to Callow up
Years
I
2
3
I
5
6
7
1- 5
6—10
11-15
16-20
21-25
26-30
31-35
No of
cases
45
64
52
21
16
1
1
Reactivation
5
3
5.77
I
6 25
I
I
J
I
/ 1078
may
tom, though, in retrospect after replacement therapy, his
gain in weight and vitality indicated that he may have
been less fit than he realised before treatment.
A corticotrophin assay suggested increased activity.
Release of corticotrophin and melanocyte-stimulating
hormone appeared to occur separately. The usefulness
of the water-load test in minor degrees of adrenocortical
insufficiency is questioned.
I wish to thank Dr. T. M. Chalmers, under whose care the patient
was studied, for assistance with the preparation of this report. I am
indebted to Prof. A. Kekwick for criticism of the text, and to Miss
Audrey Moxham for measuring the cortisol secretion-rate. Dr.
Beryl Davies kindly estimated the plasma-corticotrophin.
REFERENCES
D., Jr.’ Rosenthal, O., Dohan, F. C., Richardson,
E. M., Zintel, H. A., Jeffers, W. A. (1954) Amer. J. Med. 16, 328.
Jadrcsic, A., Carrasco, M., Ldpez, E. (1962) Lancet, i, 401.
Lerner, A. B (1955) Amer .J. Med. 19, 902.
— Shizume, K., Bunding, I. (1934) J. dm. Endomn.iA, 1463.
Najib abu Huydar, St. Marc, J. R., Reddy, W. T., Laidlaw, J. C., Thorn,
G. W. (1958)7. din. Endocrin. 18, 121.
Robi^ison^F J^Po^er’.'M.’ H.,Hepler, E. J. (1941) l\oc. Mayo Clin. 19, 902.
Preliminary Communications
is usual.
thb
INVBSTiaATXbN
INTERMITTENT TREATMENT OF
PULMONARY TUBERCULOSIS
A Concurrent Comparison of Twice-weekly
Isoniazid plus Streptomycin and Daily isoniazid plus
p-Aminosalicylic Acid in Domiciliary Treatment
Brom the Tuberculosis Chemotherapy Centre, Madras •
Domiciliary chemotherapy of tuberculosis has become
accepted practice in developing countries, but the best
method of administering the drugs is still in question.
Self-medication for long periods may result in irregu
larities, and, although fully supervised daily chemotherapy
has been used to avoid these, it imposes a considerable
strain on clinic and patients, and is hardly practicable in
developing countries (see review by Fox l). If, instead,
supervised therapy could be given intermittently—e.g.,
twice a week—the method could become more generally
Health Organisation.')
• The centre is under the joint auspices of the Indian Co^cil of
Medical Research, the Madras State Government, the World
Health Organisation, and the Medical Research Council ol
Great Britain. The research of the centre is guided by a project
committee consisting of representatives of the above agencies
and the director of the centre. The British Medical Research
Owii-il (acting through their Tubcrculoni* Reneiirch Unit) uro
KKOoiixibk Im H.lylsh.g ihe Woihl Health <hgaitlouilon on the
rwcaich. Thi* t/icllniinaiy coniinunkalion hu» been prepared
try the scnioi aciunihc stall ol the centre.
I Vox, W in Proceedingx ot the XVIth Intcrnauonal Tuberculoxtx
Conference, 1961; p 307. Amsterdam,
2. Tuberculosis Chemotherapy Centre. Bull. World nltn Org. 1960, ,
3 GMgadharam, P. R. I-, Devadutu, S., Pox, W., Narayanan Nair, C.,
’ Selkon.J.B. ibid. 1961, 25, 793.
■ ■■............................
It seemed unlikely that efficacy would be serious.?
diminished by a limited degree of intermittency, in v.c*
of our observation that patients who showed irregular...'
(on the evidence of urine tests) in taking isoniazid tn»
large dosage every day responded to treatment as well a
those who were completely regular.4 5
There is relevant experimental evidence that a
dosage of streptomycin or isoniazid given at intervals ci
five or seven days is effective in suppressing the develop
ment of tuberculosis in the guineapig.4 7 There is sinuL
evidence, in tuberculosis of the mouse, of the effective
ness of isoniazid every seven days,4 and of isoniazid plus
streptomycin every three days.*
In view of our finding and the experimental evidence
we decided to test the effectiveness of a combination u
the two most potent standard anti-tuberculosis drug^namely, isoniazid and streptomycin—given twice-weci.
under supervision, the minimum interval considered offer substantial practical advantages over a daily regimes.
Isoniazid was to be given in high dosage and strcptomyc;
was to be administered in doses of 1 g., which, in vic* a
the light weight of our patients, is a higher dosage tU
In June, 1961, we started a controlled comparison d
this supervised intermittent regimen with our stand*-,
unsupervised daily regimen of isoniazid plus P.A.S. 1 findings are of sufficient importance to mem this pre
liminary communication, which gives bacteriolog.u.
results at six and nine months. (Detailed findings at cc*
year will be published later in the Bulletin of the »cr-
applicable.
A rational basis for intermittent chemotherapy was
suggested by previous studies at this centre. In a com
parison of three regimens of isoniazid alone with a
regimen of isoniazid plus p-aminosalicylic acid (p.A.S.) i it
had been found thatadaily dosage of isoniazid (7-8-9-6 mg.
per kg. body-weight) was more effective when given m
one dose than when given in two doses. There was
evidence that this was because a high peak concentration
of isoniazid in the serum played a more important role
in the response to treatment than the maintenance of a
continuous inhibitory level of the drug? It was therefore
reasonable to study regimens in which the interval
between suitably high doses of isoniazid was extended.
X
may
THE lang:
PRELIMINARY COMMUNICATIONS
18, 1963
Chemotherapeutic Regimens
The two chemotherapeutic regimens studied were:
SHTW.—Streptomycin sulphate by intramuscular ixijecu.^
in a dose of 1 g. irrespective of the patient’s weight,
isoniazid in a single oral dose of 650 mg. for a patient wogt^
100 lb. (45-4 kg.); the two drugs were given together t*~
weekly (at intervals of three and four days). Each
of streptomycin was, on average, 27 0 mg. per kg l-_u.
body-weight (range is 18 2 to 53-7 mg.). The dosage a
isoniazid was increased for heavier and reduced for In
patients,4 the average being 13-9 mg. per kg. body-wc*initially (range 12-5 to 16-1 mg.).
PH —Isoniazid 200 mg. daily plus P.A.S. (sodnun salt k i
daily in 8 cachets (4 in the morning, 4 in the evening1 u i
patient weighing 100 lb. or more. The dosage was red-.:for lighter patients?4 The average daily dosage ot isoni^
was 4-4 mg. per kg. body-weight initially (range T7 to 6 3
and that of P.A.S. was 220 mg. per kg. (range 180 to 3.0 cq
Management of the Patients
The patients in the shtw series attended the centre >
clinic twice a week and received an injection of strcf>
mycin; a dose of isoniazid was given at the same la
under the direct supervision of the clinic staff. 1-*
PH patients attended the clinic once a week k. •
supply of cachets, which were to be taken at home. other respects the management of the patients in ixu
series followed the same lines as in a previous invesugLx..
at this centre? All the patients were to be treated
outpatients for twelve months.
Aniong other pioccdurcH, Hpcciuwus of sputum - >
■I
rHbuoiloxlxCheiimilivnipyVtfiilis Hull
7. Palmer, C. E., Ferebec, S. H., Hopwood, L. Amer. Bev. l^.
74 917
J:
18, 19e
examined ba
thereafter. 7
Jensen medii
viously.* For
been assessed
(overnight) ai
obtained at sii
Definition of 5
The patier
City as bef<
criteria as in
bacteriologic;
admission, w
known had e
chemotherap
weeks.
Patients Admit
In all, 165
cedure eithe
patients) or
patients have
they had beet
to the invest
resistant to i
resistant to
resistant to
(79 shtw, 71
Condition on .4
The age, sea
tabulated here)
Table t shows
logical conditu
from single ful
KDr. J. Frimoe
scries of any j
24% of the 79
71 in the ph ser
U'ith regard to
SHTW series an'
disease; 48% ;
zones involved
content of the
»ere also simih
direct smear c
3-plus positive ;
Hi series, respe
TABLE I—RADI
Condition on ,
Extent of caviutioi
Nil ..
Slight
Mudcrute
Extensive
T»<d extent of dix
Trivial or slight
Limited or mode
Extensive or gro:
.’•amber of lung zo
1. 2 or 3
«, 5 or 6
u-nal voiucnt o'
Fust o» vuly ” vol
I’llVCt SIUCUI lu-g
OllVx't •IlKUl IK'S
1- plui tivauty)
2- plus Uuodcr
3- plus (heavy)
•
W 18, 1963
THE LANCET
be seriously
tency, in view
cd irregularity
isoniazid in a
nent as well as
:c that a high
nt intervals of
ig the dcvelop4'hcre is similar
f the effectivcf isoniazid plus
tcntal evidence,
combination of
culosis drugs—
n twice-weekly
1 considered to
a daily regimen,
id streptomycin
hich, in view of
icr dosage than
i comparison of
h our standard
plus r.A.s. The
merit this prebactcriological
1 findings at one
tin of the World
tudied were:
nuscular injection
:nt’s weight, plu»
a patient weighing
■cn together twice
days). Each dose
g. per kg. initial
. The dosage of
educed for lighter
kg. body-weight
(sodium salt1) 10 r
the evening) for ■
osage was reduced
dosage of isoninrid
ngc 3 7 to 6 3 mg ),
’e 180 to 320 mg '
I
PRELIMINARY COMMUNICATIONS
"umined bacteriologically before treatment and monthly
ptreafter. These specimens were cultured on Lttwenstein•nsen medium according to the procedure described pre•mly.* For the purpose of this communication, progress has
-tn assessed only by the culture results of two “ collection ”
Ttmight) and one supervised “ spot ” specimen of sputum
Gained at six and at nine months.
''r'inition of Suitable Cases
The patients were drawn from the same area in Madras
jty as before.*41' They all conformed to the same
sitcria as in the earlier studies. In particular, all had
•jcteriologically confirmed pulmonary tuberculosis on
Emission, were aged 12 years or more, and as far as was
cwn had cither received no previous anti-tuberculosis
^motherapy or had received it for not more than two
1 rttks.
1 ':tients Admitted to Study
In all, 165 patients were allocated by a random pro
cure either to the intermittent regimen (83 shtw
inents) or to the daily regimen (82 ph patients). 15
irients have been excluded from the analysis because
'ty had been excreting resistant organisms on admission
'the investigation; 7 (3 shtw, 4 ph) had organisms
ustant to isoniazid, 5 (1 shtw, 4 ph) had organisms
Tstant to streptomycin, and 3 (all ph) organisms
distant to both drugs. There remain 150 patients
3 shtw, 71 ph) for analysis.
-dition on Admission
The age, sex, and weight distributions of the patients (not
plated here) were similar for the two series on admission,
de I shows their pre-trratment radiographic and bacterior.-al condition. The radiographic findings were reported
? ,sin|lc fulI-Plate radiographs by an independent assessor
... J. Fnmodt-Moller), who was unaware of the treatment
of any patient. He graded cavitation as extensive in
i’. of the 79 patients in the shtw series and in 15% of the
a the ph series; 5% and 6%, respectively, had no cavitation,
•h regard to total extent of disease, 28% of patients in the
’T senes and 31% in the ph series had extensive or gross
'ase; 48% and 52%, respectively, had four or more lung
involved in disease. The distributions of the bacterial
Trent of the first (or only) collection specimen of sputum
-Also similar. Thus, 10% of both series were negative on
-4 smear examination; the proportion with 2-plus or
•us positive smears were 67% for the shtw and 72% for the
•'tries, respectively.
■•BLE I
RADIOGRAPHIC AND BACTERIOLOGICAL CONDITION ON
ADMISSION TO TREATMENT
SHTW
Condition on admission to treatment
nded the centre**
ection of streptoat the same time
clinic staff. The
e a week for a
ken at home. !n
: patients in both
vious investigation
to be treated
of sputum wrrr
dHlth Org. (in the t-'’*
he press).
, 446.
4”irr. Rev. Twhe-r I***
1052. R3.
l<i HhhOrf. 1050.
PH
■%
No.
No.
%
-nt of cavitation:
’rht
............................ ..
‘derate...............................
rtnsive ..
..
..
*‘
*’
”
■> extent of disease:
-nd or slight..........................................
--'ted or moderate
..
..
rtnsive or gross..............................
•ler of lung zones involved In disease:
'or 6
4
26
30
19
5
33
38
24
4
26
30
11
6
37
42
15
6
51
22
8
65
28
1
48
22
1
68
31
..................................
41
52
34
48
38
-il content of sputum:
-eronly " collection ” specimen):
specimen):
n.n smear negative
net smear positive:
•plus (scanty) ..
11-Nus (moderate)
| ‘■phis (heavy)
Tot«! patients
48
37
52
8
10
7
10
18
41
12
23
52
15
13
44
7
18
62
10
100
71
100
THE LANCET
1079
TABLE II—PRESENCE OF TUBERCLE BACILLI IN MULTIPLE SPUTUM
SPECIMENS AT SIX AND NINE MONTHS
Months after
start of
chemotherapy
Treat
ment
series
Total
patients
(A)
Tuber
culous
death
Patients with
at least one
specimen
positive on
culture
6
SHTW
PH
77
68
2
1
10
SHTW
PH
72
65
2
1
9
Patients with
all cultures
negative
No.
% of A
0
65
58
84
85
3
6
67
58
03
89
RESULTS
Deaths
3 patients died of pulmonary tuberculosis, 2 (1 shtw,
1 ph) in the first week, and the third (shtw) in the sixth
month. This patient’s sputum was culture-negative at
three and four months, but she had a serious radiographic
deterioration in the fifth month (no culture results were
available at five months). One other patient (ph) died
suddenly from a non-tuberculous cause (believed to be
pulmonary embolism) in the eighth month; the sputum
had been culture-negative from one month. Permission
for necropsy was refused for all 4 patients.
Premature Termination of Originally Prescribed Chemotherapy
3 patients (all ph) had their original regimen terminated
for drug toxicity, 1 in the first, 1 in the fifth, and 1 in the
ninth month. 6 patients (5 shtw, 1 ph) became
uncooperative and stopped the treatment, 2 (shtw) in
the third month, 1 (shtw) in the seventh, and the other
3 in the eighth month; in 3 of the shtw patients
streptomycin toxicity may have been a contributory
factor. '
The patient who died from a non-tuberculous cause in
the eighth month has been included in the analysis at
six months, and the 9 whose originally prescribed
chemotherapy was terminated prematurely have been
included up to the time of the termination. The patients
who died of tuberculosis have been retained in the
analysis.
Bacteriological Findings
The results of culture examination of the sputum
specimens at six and nine months arc shown in table n.
(Apart
from themoovc
aboveexclusions,
exclusions,results
results; arc not available
v
•i'"*L
for 1 P«ticnt (-phJ- at six months---------and 3Jf2SHTW, 1 PH] at
J--------• ' —
•
nine
months.)
The
average number of culture results
per patient was 2-7 in each series at six months and 2-8
in each scries at nine months. At six months all the
cultures were negative in 84% of 77 shtw patients, com
pared with 85% of 68 ph patients; at nine months the
corresponding figures were 93% of 72 and 89% of 65,
respectively.
Drug Toxicity
2 patients in the SHTW series had toxic symptoms attributed
to isoniazid. One patient had convulsions a few hours after
the administration of chemotherapy on two occasions in the
first two months of treatment; these did not recur after
pyridoxine in a dosage of 6 mg. twice weeklv was added to the
chemotherapy. The other patient first complained of symptoms
attributable to peripheral neuropathy in the second month;
pyridoxine in a dosage of 6 mg. twice weekly was given with
the chemotherapy with subsequent improvement in the
clinical symptoms and signs. Complaints of giddiness were
recorded in 24 of the 79 patients in this series (7 of 71 ph
patients also complained of giddiness), once in 15 of them and
on two or more occasions in 9. In 5 of the latter it was
necessary to reduce the high dosage of streptomycin to
approximately 15 mg. per kg. body-weight for each dose; 4 of
the 5 remained under treatment to the end of the period.
i
)
<
4
I
J 080
MY 18, 1963
PRELIMINARY COMMUNICATIONS
3 patients in the ph series developed hypersensitivity
reactions to p.A.S. in the early weeks of treatment; as noted
above, it became necessary to change to a different chemo
therapeutic combination. Desensitisation was attempted and
was initially successful in 2 patients; however, both again
developed reactions which could not be controlled. All 3
patients received prednisone.
THE LANlL
*UY 18, 1963
of streptomycin in 5 patients because of giddiness. In I,
INVE
other patients who reported giddiness, it was not consider;
blood
-f
necessary to reduce the dosage, and in most it is uncerua
how lar, if at all, their complaints were due to the strepcomycu
RADIO/
Isoniazid caused convulsions in 1 patient and peripheu
AND E
neuropathy in 1 other; both responded to 6 mg. of pyridom
In essential h
given twice weekly with their chemotherapy. Probably t.--the cerebral oxy
isoniazid toxicity could have been prevented if this small lx
DISCUSSION
by the Kety-Scli
ol
pyridoxine
had
been
given
from
the
start
of
treatment.
*
In the treatment of pulmonary tuberculosis with
by the results
In the PH series 3 patients developed hypersensitivity l
combined chemotherapy, it is standard practice to give
reviewed in det
P.A.S., and their original treatment had to be terminated.
the two or more drugs in one or more doses daily;
cerebral perfush
5 of 79 patients on intermittent chemotherapy becanx
regimens consisting of one drug (isoniazid or p.a.s.)
variations of bio
uncooperative and stopped their treatment. The reasca
given daily and another (usually streptomycin) given on
die normal chem
are uncertain, though streptomycin toxicity may have
two or three days a week are no longer regarded as
'The converse
been a factor in 3. A fuller assessment of the acceptabihn
adequate by most authorities.
fundamental in i
of the intermittent regimen should be possible when th:
There have been a few reports of studies in which the
been suggested b
findings for one year are available, but it will be difiic-.:
entire medication, whether with a single drug or a
of eighty cadaver
to
make
valid
comparisons
with
the
regimen
for
daw
combination, was less frequent than once a day.
between the ante
self-medication.
I’runodt-Muller et al.11 compared isoniazid alone every
fluid-carrying ca
The encouraging therapeutic results of intermitter
fourth day with the same dosage given daily, and found
carotid arteries,
chemotherapy in this trial suggest that a change z
sinular radiographic responses in the two series at twelve
gested that ceret
orientation of drug administration for tuberculosis nu
weeks.
but this suggestio
Katz et al. 111 and Chambers et al.18 treated a small group of become possible in the developing countries, from cz
a series of norni<
present daily self-administration to twice-weekly lu;
patients with streptomycin 2 g. plus isoniazid 500 mg., both
found that the
supervised administration. The next steps for consider- I
being given together by injection twice weekly. They con
ophthalmodynomi
sidered that the radiographic and bacteriological improvement
ation include study of dosage and acceptability in grearc
brachial-artery pr
was inferior to results achieved previously with daily isoniazid
detail and of a decrease in the frequency of administrate I
plus twice-weekly streptomycin.
to once weekly. Once-weekly regimens are now betq 1 conscious ambul.
Tyrrell 14 gave newly diagnosed cases streptomycin 1 g. and
investigated at this centre; if this frequency should prove I probably never a <.
Recently, Brod
isoniazid 400 mg. on the same day twice weekly, half being
successful, it would offer further advantages, z I
treated in hospital and half as ambulatory outpatients. At six
convenience for the patients, in economy, in applicable:. I that any considers
months, sputum conversion had occurred in 78% of 45
to mass treatment, and possibly in decreased toxicity.
I tension should be
inpatients and in 80% of 46 outpatients; there was no
ol hmmodynaniic
comparative group on daily drug administration.
Jubjects in as many
SUMMARY
Holmes et al.14 reported on 29 patients given a large dose
165 patients were allocated by a random procedure a I data on cardiac ou
of isoniazid once a week for periods of up to three months,
an
intermittent chemotherapeutic regimen of suepu- I dtin, and muscle.
but only 2 became culture-negative.
We have develo
mycin plus isoniazid given together under supervisee I
Streptomycin plus isoniazid, the two drugs being given together
applicable
to output
twice weekly (shtw regimen, 83 patients) and to i I
every other day, has been used with success by Mackay-Dick
dace
regional
cerebr
standard regimen of p.A.S. plus isoniazid for daily seJ |
and his colleagues,1'' “■ and by Hutton et al.1"’; but in these
administration (ph regimen, 82 patients).
15 paticcu I the sensorimotor co
scries the intermittent regimen was used as continuation
(4 shtw, 11 ph) have been excluded from the analvw I been studied in elew
. therapy after a period of one to three months of daily combined
chemotherapy.
because they had organisms resistant to streptomycin . I investigation show
disease, and the d;
isoniazid or both at the start of treatment.
In our controlled study, streptomycin plus isoniazid,
obtained in a series
both drugs being given together twice a week in high
This preliminary report gives the sputum-cuk-r: I
dosage under supervision as a primary treatment (shtw
results at six and nine months.
regimen) has proved to be therapeutically as effective as
The method, which
The pre-treatment status of the patients in the t.
umilar in principle to
the standard oral two-drug regimen of p.a.s. plus isoniazid,
series was similar in respect of a number of fact...
lhese workers injecte
prescribed for self-medication daily (ph regimen).
examined—namely, age, sex, weight, radiographic findin,
*nd measured the rat
Although results are at present complete only up to nine
and bacterial content of the sputum.
•crebral cortex at crani
months, there is no reason to think that the position will
3 patients (2 shtw, 1 ph) died of pulmonary tuberculou.
Hxwe the exposed tissi
be different when all the results at twelve months are
,MXe (half-life=5
At six months all the cultures were negative for 84 . a
available.
MeV gamma radiation
77 shtw patients compared with 85% of 08 PH pallet-.
Evidence of toxicity was seen in some patients in both
atracranially by using
The corresponding proportions at nine months v»c.
series.
-'t fitted with a thal93% and 89%, respectively.
Mcasurements are usua
In the shtw series, it was necessary to reduce the dosage
2 shtw patients had isoniazid toxicity, treated w.u
between the external au
11. Frimodt-MuJier, J., jesudian, K. T., Muthiah, T. S., Barton, R. M.
6 mg. of pyridoxine twice a week without interrupt-:,
is administered t
bid. J rubcrc. 1953, 1, 23.
the regimen; in 5 shtw patients the dosage of streptuir...antaining 0-5 mC per
12. Katz, S>.» McCormick, G.,deLeon, A., Gruver, R., Stanton, J., Bakir, F.,
Marshal), E.m I ransactions of the Xlllth Conference on the Chemodosed-circuit system,
was reduced because of giddiness; and 3 ph patients
f‘*l?Y of T uberculonu; p. 355. Washington, D.C., 1954.
aid at the same time
13. Chambers, J.. Katz, S., McCormick, G.. Gimblc, A., Leonard, I.,
their originally prescribed treatment terminated for f i.
Schmidt, W., Shea, J in 1 lunsacliuns of die XlVlh Conference on the
*>m the blood-stream,
toxicity. 6 uncooperative patients (5 shtw, 1 ph) stop,-.udc air. 1'he cuuut-rm
treatment.
This
may
have
been
partly
due
to
streptomv.-;
1’“■1 ■
'■
«• K«y.S.S.,S<hnud[,c
toxicity in 3 shtw patients.
16. Mackay-Dick, J. Lancet, 1954, ii. 44.
1 Dukrnsvii
N AA\.
C. J., Thomp
17. Mackay-Dick,). Hrii.mcd.J. 1959, ii, 100.
The encouraging results of twice-weekly supervu-. : ‘1 Lowe,
R. D. .bid. i90i/■
18. Todd, G., Teare, D., Gordon, W. 1. Lancet, 1956, ii, 1.
chemotherapy in this trial suggest that a change .
19. Eade, A W. T. Harrison, G. K., Large, S. E., Mackay-Dick, J.,
• >r<Mi.
Fend. V., f(rp
Reid. L. McA.. Riddell. R W. TAi-ra.v, 1959, 14, 104.
orientation of drug administration for lubcrculw- »
’ "avur.O.
2 rXr'V/S^ Vvso’a?' IM’ W‘l,wn”■
1- M„ Fox, W,
developing countries may become possible.
‘ HMlbcrg. L., Veall, N.
f FcuAVS-aCA. -»->A
> '■A
BuUenn of
World Heal,„ Organization 21 (1959) 5J
-14^
Excerpts from:
OF
COMPAR«ON
op po“m°—"Sasx,,
*
BY
discussion
res™'
XT'™ Wth ‘h=
for a penod of 12 months .h ej'me'» of patients
/
be appreciated that th^
'n sanatorilJni.
,l(,c '"formation, obtained froS^'1 ^'^^atively
tr‘als, on the value of chemnr COntro,,ed clinical
culosis Society Of Scotland "9™')'“
‘hc Tul«r.
^Pics or in under-develoned '
Py
in the
esults
of
a
study
of
chemothem
reported
mterim
hospital studies reported, Or"tneS’apart from
ome or in hospital for a minimn ?
bed'rest at
(Hutton ct al. J95<s. F/,
d from East Africa
months, in comparison with X
of three
Svvithinbank, 1957- East^ Af3’ ’ ,956’ Howe/,s &
'n Patients permitted X
Chcm°*eraPy
Research Council SulphonC ;“n/Br"“h M«tal
■‘fe. Acutely ill patients wem
normal working
and from India (Pr;
,nvesl,gation,
n, 1959)
1959),
indies,
which
are
hardly
comnrL
3
^^^
tO thes«
R-odt-MoX
’
■
1949, 1955;’}*
mvestigation, in which' th^
W‘tb the P^ent
fa rev,ew °f the world literal unb Furthcrmorc,
Patients had moderately advanr f rnajorit>' °f the
controlled studies of the reL
Ta,ed that
disease, all had symptoms
7 °r far advanced
™ and ambulation in the tr^
6 Va,Ue of b*dJnberculosis have so far hJ'eatment of pulmonary
Furthermore, treatment was for
Append”0<
1957) reporter XT'?'
months and, jn addition i,
3 Per'od of 12
h<,me for a second 12 months r0'"8 Continued
at
TOrai" —
in both
-J prc-
“‘V’a —
X’si nl7ny were c^i.
.X.;— ““i”
from Bulled of th,
Pubhcat.ons, WHO, Geneva ,e
Hea“h
(59) 5,-,“-
------------- -Chief Office of
HOME AND SANATORIUM CARE OF TUBERCULOSIS
vention. Finally, the social conditions of our
patients were very different from those in the Ame
rican and British inquiries.
For the present study it was decided to use a
standard form of oral chemotherapy—namely, iso
niazid 200 mg daily together with PAS (sodium
suit) 10 g daily, for patients weighing l(X) lb. (45
kg) or more. The dosage was reduced for lighter
patients, and ranged from 3.7 to 6.6 mg/kg body
weight for isoniazid and from 0.19 to 0.33 g/kg
for PAS (sodium). The drugs were given together
in the same cachet and were prescribed in two
doses daily. This combination was chosen because
it is administered orally ; it is known to be effi
cacious ; it is not associated with a high incidence
of side effects or toxic manifestations ; and because
it has been used in controlled clinical studies, so
that much is known about it in relation to other
regimes (Great Britain, Medical Research Council,
1953b, 1955 ; Bowerman, 1957 ; East African/
British Medical Research Council Sulphone In
vestigation, 1959). The combination was given to
the patients in both series, so that the essential
comparison was of treatment at home with treat
ment in sanatorium for 12 months, the patients
receiving the same standard chemotherapy through
out this period.
123
the disparity was greater for females than for
males it has been necessary in this report to present
the results separately for the males and females
in the two series, and, in addition, to make special
investigations of the influence of the pretreatment
differences on the response to treatment in the two
scries. The risk of such differences- might be re
duced in future studies, especially if a wide range
of disease types is being studied, by classifying the
patients on the basis of the radiographic appear
ances and then allocating treatment at random
within each class.
The most important finding is that even though
the 49 males in the home series were at a disadvantage
in respect of the radiographic features and bacterial
content of the sputum when treatment started, as
compared with the 50 males in sanatorium, there
was little to choose between the progress of the
males in the two series over the 12-month period.
The sanatorium patients gained much more weight,
as might have been expected, and the response of
the erythrocyte sedimentation rate was greater.
Nevertheless, the radiographic and bacteriological
responses, which are the important assessments,
show at most only a slight benefit to the sanatorium
series. At the end of 12 months, 10% of the patients
in each series had bacteriologically active disease,
In all, 96 patients were allocated to treatment at^ on the basis of very stringent criteria.
home and 97 to treatment in sanatorium, by a
Because of the major pretreatment differences
process of randomization. Of these, 82 at home and
already referred to, it is less easy to interpret the
81 in sanatorium form the basis of the main ana
direct comparison of the results of the treatment for
lysis in this report. These were the patients who had
females in the two series. These results showed
organisms sensitive to both drugs at the start of
definite radiographic and bacteriological disadvan
treatment, maintained that they had had no pre
tages to the 33 treated at home, compared with the
vious antituberculosis chemotherapy, or chemo
31 in sanatorium. When allowance was made for
therapy for less than two weeks (despite question
pretreatment differences by statistical standardiza
ing on several occasions during treatment), and
tion, the radiographic responses were similar in the
followed the prescribed course of treatment for
two scries, but the bacteriological disadvantage to
the full 12 months.
the females at home persisted. Taking these findings
into consideration, it has been concluded that any
Although the process of randomization was
difference which may exist between the response to
strictly observed, important pretreatment differ
ences were, in the event, found between the two
treatment at home and the response to treatment in
series of patients. The differences were in respect
sanatorium for females in similar clinical condition
of the extent of cavitation and the total extent of
before the start of treatment is small.
disease radiographically, and in the bacterial con
Summarizing the position for both sexes together,
tent of the sputum. Although slight chance differ
it is apparent that treatment at home gave results
ences in pretreatment condition are to be expected
closely approaching those of treatment in sanatorium
in studies based upon random allocation of treat
and that the differences between the results of
ment, large differences in important criteria, as
home and sanatorium treatment were surprisingly
in the present study, represent a most unusual
small.
occurrence. The pretreatment differences have
It should be noted that these satisfactory findings
complicated the analysis of the present data. Since
in the home patients have been obtained even though
124
TUBERCULOSIS CHEMOIHERAPY CENTRE
the majority had major lesions, and that a high
treatment, also do not appear to have afTected the
outcome to an appreciable extent.
proportion had unfavourable clinical features when
treatment began. The patients who did not attain
bacteriological quiescence had, in the main, extensive
disease and cavitation.
It seems very likely that if
it were possible, cither as a result of mass radio
graphy, or of propaganda directed at the general
public and the medical profession, to diagnose the
disease in its earlier stages, the results of domiciliary
treatment might be even better than those reported
here. It^is also possible (hat better results could
be obtained, even with a group of patients as ill
as those in the present study, if the chemotherapy
were changed to another combination when patients
appeared unlikely to convert their sputum
bacteriological negativity on isoniazid plus PAS.
to
it has generally been considered that a good diet,
satisfactory accommodation, adequate rest and
nursing care together make an important contribu
tion to the treatment of tuberculosis, and that they
represent advantages of sanatorium treatment.
In the present study, the patients treated at home
were at a major disadvantage in all these respects
but. despite (his. they fared remarkably well; these
factors appear to have had little inlluencc on the
results of treatment.
It has been established that there were major
differences between the two series of patients in
tespect of did during the cotuse of the 12 months
the sanatorium diet being balanced and clearly
superior. It will be possible, when the data have
been analysed in detail, to study whether the attain
ment ol bacteriological quiescence or the pcisistcnce
of active disease is related to the diet of the patient.
It is. however, already apparent that despite diets
vvluch weic deficient in impoitant faclois. notably
the protein content,
------- the patients at home, as a
group, made good progress, On the other hand,
the control group
i-------- :in
- sanatorium, despite having a
balanccd diet, with an adequate
protein content,
and making substantial weight gains, derived
surprisingly little additional benefit.
I he i ole of
diet in the attainment of ultimate cure, however, has
still to he investigated.
It has also been shown that the accommodation
of the majoiil^v ol (he home patients not only before
but during ticatment was very unsatisfactoiy, a high
proportion living in conditions of overcrowding.
In addition, the home patients, especially the females,
had less rest and rcltnned to active work eailicr’
Ihesc further dillercnccs, which arc usually regarded
as predisposing
to an unfavourable response to
An advantage of treatment in sanatorium is that
the administration of medicines can be supervised,
and, apart from major toxicity, no difficulty with
the administration of medicine was encountered in
the present study. However, an unexpected problem
arose in persuading the home patients to take the
medicine regularly, especially once they felt well
This occurred even though great emphasis was laid
on (he importance of regularity by all the clinical
stall and although most patients attended the Centre
regularly for their weekly supplies of medicine and
their monthly examinations. In order to supervise
the self-administration of the medicine, urine tests
for PAS were introduced, and also counts were made
of the patients’ stock of cachets to see that the
correct number remained. The most valuable checks
by both methods were those made at surprise visits
to the home. Although there was good evidence
that a number of the patients were irregular in taking
'.heir medicine, it has not been possible to show
that this was associated with clinical disadvantages
during the 12-month period; however, the possibility
of subsequent clinical disadvantages still remains
to be studied.
But even if moderate irregularities
arc ultimately shown to carry little long-term dis
advantage, there must obviously be some level of
intake below which ii icgulaiitics do become impor
tant. I hus, in any scheme for domiciliary treatment
depending on the self-administration of medicines
paidcular emphasis should be laid on the importance
"I regularity m taking them. Moreover, the present
study has shown (hat mere regularity in attendance
at a clime docs not necessarily mean that the patient
is co-operating by taking his medicine. Dillicdlty
with the self-administration of a combination of
isoniazid and PAS in Britain has been reported by
S-mpson (1956), Dixon, Stradling & Wootton
(195/), and Wynn-Williams & Arris (1958).
In contrast to these disadvantages of treatment
•il home, two unexpected advantages became ap
parent during the course of the study. The first
advantage of treatment at home in this study was
sociological. A detailed and careful sociological
record was kept for each family. Whereas major
problems were encountered in eight of the 96 home
families, they arose in 20 of the 97 sanatorium
families. Moreover, the sociological dilliculties in
the families of sanatorium patients were usually
more serious than those in the families of patients
treated at home.
For example, there was one case
HOME AND SANATORIUM CARE OE TUBERCULOSIS
of infidelity in the home series, but in the sanatorium
scries there were six cases, anda suspicion of infidelity
of a spouse in three more. There is little doubt that
the long-term sanatorium treatment of patients in
125
The conclusion from the present study that (except
lor some of the most severe cases) it is possible to
obtain good results, al least fora pci iod of 12 months,
from treatment at home has practical implications.
this particular study proved disruptive to family
Provided it can be shown that relapse is infrequent
life, and this must be considered a disadvantage of and that there is no special risk to contacts if patients
treatment in the sanatorium series.
are treated at home, and provided that the results
The second advantage concerns the co-operation
oi this study would apply in other communities,
of the patients. When this study was being planned,
there may be little to gain from admitting the
the general consensus of expert opinion, both in
general run of patients to sanatorium. There would
Europe and India, had been (hat it would he very
still remain, however, a need to admit selected cases
dillicult to obtain the co-operation of a high propor lor in-patient care for example, gravely ill patients,
tion of any group of patients in treatment at home,
patients suH'cring from complications such as
even for as long as three months, but that patients
haemoptysis or spontaneous pneumothorax and
would welcome treatment in sanatorium. In the
those needing special management, such as pregnant
event, only one of the 96 patients allocated to treat
patients and those for whom it is decided that
ment al home, compared with seven of the 97 patients
surgciy is necessary. The management of the more
admitted to sanatorium, was lost from treatment
seriously ill patients who were treated at home in
during the 12 months. In five more sanatorium
this study would certainly have been easier in sana
patients there were interruptions in (he sanatorium
torium, since this would have given greater control
stay, although these did not necessitate the exclusion
over the patient and his treatment. If domiciliary
of the patients concerned from the main analysis. It
treatment is embarked upon on a large scale, it
proved much more dillicult to persuade male patients
would also appear essential to have access to a small
to remain in sanatorium than female patients, 10 of number ol hospital beds for non-tubcrculous condi
the above 12 sanatorium patients being males. This
tions. In the present study it became necessary to
difficulty in persuading patients to remain under ‘ admit 13 (13%) of the home patients to hospital,
treatment in sanatorium for a long period of time,
mostly for short periods only, for the investigation
despite a very active welfare service for the patients
or treatment of such conditions.
and their families, must be considered a major
It cannot be assumed that any routine tuberculosis
disadvantage of the sanatorium treatment. However,
clinic would automatically obtain results approach
without the highly oTganized domiciliary service
ing those reported here. The experience of this
which concentrated on persuading patients to
Centre suggests that certain minimum facilities are
attend, especially when there were signs that they
necessary for the satisfactory organization of an
were becoming inattentive to treatment, it is certain
cllicicnt domiciliary service based on a tuberculosis
that in this study a considerable proportion of the
Anion15 these facilities arc an adequate supply
home patients would have stopped treatment.
of medication, and alternative medicaments for
In view of the poverty of the patients and their
patients who are not responding satisfactorily ;
families and the need Io keep (heir co-operation, a
enough stall' to supervise the patients, including a
limited amount of financial assistance was given to
social worker and a public health nurse; an cllicicnt
more than half the families, as the main earner in
appointment system, so that it is known when
the family often had to remain off work for several
patients have failed to attend; adequate transport
months or in sanatorium for a full 12 months. This
for the senior clinical stall to visit ill patients, or
financial assistance to the families was never above
patients whose co-operation is flagging; an ambul
a modest level. As might have been expected, the
ance for ill patients; a small number of hdspital
families of male patients in both scries needed more
beds for special or emergency cases; an organized
financial assistance than the families of female
system of surprise visits to the home to collect
patients, and more assistance was required for the
specimens of urine to test for the presence of the
families of patients at home than for those of drug and to check the stocks of medicine; a labor
patients in sanatorium. It seems likely that this
atory capable of performing, as a minimal require
assistance contributed to the good co-operation of ment, large numbers of reliable smear examinations
both series of patients, although it did not succeed
of sputum for tubercle bacilli; and the resources to
in preventing the losses from sanatorium.
give at least limited financial assistance in cases of
126
TUBERCULOSIS CHEMOTHERAPY
nreTn!'ar '’"T’’ SinCe “ proP°rtio" <>f Patients will
present m a destitute condition. Without adequate
facditics and dose supervision of the patients the
results of donuciliaiy treatment might well fall far
below those reported here.
Toxic and hypersensitivity manifestations . were
infrequent m this study, occL..:..b ... _
CENTRE
following previous treatment, fared rather 1<
than patients who had had no previous
therapy and had sensitive organisms.
I here was a group of patients with initia
sitive strains who repeatedly yielded positi
lures in the
PAS Th 193 rt,CIltS; 3,1 Were aftrit>utable to represented 10% of the survivors at 12 ni^
PA^ Thts accords with other experience with this
should be regarded as a potential public healt
combmation of .soniazid and PAS (Great Britain
The catalase activity of the strains from these p.
Mcchcal Research Council, 1953b. 1955; Bowerman,’
°f particular interest in view of the assoc
1957, Tuberculosis Society of Scotland, Research
between the catalase activity of tubercle bacil
Committee, 1957). Although the incidence is low
hem viru ence to the guinea-pig, and possibh
Recurrence of manifestations which were pos
to
man (Middlebrook & Dressier, 1954; Schv
sibly toxic in origin complicated the management
& Vandra, 195«). 1 he tests showed that the res
of pahents, especially under domiciliary conditions
strams from nine of the 16 patients had n<
since patients at home were only too ready to blame
catalase
activity, and so may have been virulent
all untoward symptoms on their medicine The
The
possibility
that atypical mycobacteriapat'ent ,ost from the home series during (he
is, mycobacteria other than Myco. tuberculo
12 months discharged himself because he developed
might be occurring in the patients under study
jaundice, which he attributed to the medicine.
might indeed be the cause of their disease ’
The patients and their relatives were interrogated
particularly
investigated. A range of identify
bout previous chemotherapy on several occasions
during the course of treatment, and other detailed ■tests was undertaken on a sample of the path
and hese will be the subject of a separate ref
RR^nes were often made. After excluding any
In addition, the colonial appearances of the gro
patients who might possibly have had previous
on _
Lowenstein-Jensen medium, the results of
antituberculosis treatment,
nii c , . .
----------- - activity of the stra
all of which were investigated as a matter of rou
to IAS in 2.6% of patients/and to .■
[H 2.2% of patients. Despite the dillicuhy 'in esmbme organisms wcic in fact tubercle bacilli. On
hshmg the facts with certainty, it is believed that
basis of these findings it is believed that atyp.
no patient who had had previous chemotherapy is
organisms were not cultured before the start
included m these percentages. The ligures may be
treatment from any patient in this study. Cultu
compared wnh tho.se obtained in the National Drug'
containing small numbers of mycobacteria otl
Resistance Survey in Great Britain (Fox et al., 1957)
than tubercle bacilli were obtained occasiona
which used the same methods of sensitivity testing
during
the course of treatment.
and had the same criteria of resistance; that survey
...^In.C3L'.POSitive’ but cu,lure-negative, results, whi
w in"
-7 -y uncommon1 before uthe
,c SIarI
start 0
of, trea(TOi
treatmei
to streptomycin in 2.3% in Great Britain in 1955 56
thera3*6 J? freque"cy dur,ng the earlier months
It should be noted that the incidence of
therapy> Jbecom,ng ’“S common again in the secot
resistant
resistant strains
strains was considerably higher in Madras’ th^hc^c' sn det3’led ana'ySiS °f thC d3ta SU88CS
-956-57
in
...u-,/ in
in the
me patients
patients understudy.
under study. In
In addition
o such patients with primary drug resistance, .there
and PAS, represented non-viable bacilli; they wei
are undoubtedly many patients who have had
thus classed as bacteriologically negative results.
previous chemotherapy, and have drug-resistant
Information has accumulated during the cours
organisms as a consequence, who would present
of the study which suggests that Indian strains o
themselves as new cases of the disease if a mass
tubercle bacilli differ from British strains in thei
campaign were embarked upon. It is therefore of
behaviour in PAS-sensitivity tests. It seems likelj
interest that there was evidence from a small number
that H will prove necessary,? in the case of Indiar
of cases m th.s study that patients who presented
strams, to use standards for resistance which are
isoniazid-resistant organisms, whether primary or
different from those in current use when classifying
X
,rc:"'r"C"'’ Provide<l CVidcnc' -
HOME AND SANATORIUM CARE OF lUBFRf ui.OSIS
British strains.
127
Further work on this subject is in
progress and will be reported later
neX'/f’ ‘hC reSl"lS rePOr‘Cd hcre rda‘c only to a
period of one year. A second year of treatment is
ng investigated in order to study relapse and its
prevention, and these results will be reported I Her
Funher. .he s.udy of lhe contacts of bod Xe ' of
home are exposed to special risk of infection. The
invV"|1" 1LI'ipy (ei,lre ,s ;«iso undertaking further
ustigations into problems of domiciliary chemo
herapy; a controlled study of the relative merits of
d fferent chemotherapeutic combinations in domi
Parents, wh.ch is also in progress, will give mforma
<»n on whether the contacts of patients treated at
SUMMARY
>■ In all, 193 patients were admitted to
f compdiison
of treatment at home (96 p
in sanatorium (97 patients) fopaiicm.s) win, (iciiimcrn
' Ta period of 12 months,
the patients being allocated
at random to one of
these two treatment series.
2. Patients in both series were given the sanw
Chemotherapy for the 12 months -namely ,son az d
examined 9<‘/ of .
for l^ter pa.^ ^an^dZ^i^Z
logiuU slau,s al dk end^n'l’nioX "lO'/'Xhc
aX
- -m
“ch series had died of tuberculosis
Hr^a«-^r^
cause
!b=i^^;“rXppya"d(-
differences
between
the
pretreatment
differences
criteria. ei,bt (24%)
wFrf
kU'dlv0"1"" Pa"’C'’,S t,ad aClivc disca« bacuno-
°f ,,,C
tubercufos^s
Sa"a,onilm Pabenl (3%) had dicd ()f
SSHSFr”*-■=
although the series were sim^ in‘X ~
‘he pretreatment
of
Kihad
S/X'r"ssC At'12 radip'’hic and bacterio"”
24 September
random allocahon^rtrXn^
honi Cl,hurw were
the X
were greater for the females than for the males/5
6.cai disadvantage to the female’s at home “S’
the 50 malpQ in
were compared with
“d Wi<leSPread di«a“ »nTto
u
change
....-
128
10.
TUBERCULOSIS CHEMOTHERAPY CENTRE
The self-administration
of the cachets
was
19. 7 he majority of the home patients were li\
in overcrowded conditions, the families of 68?,
supervised both by tests on the urine and by counts
of the stock of cachets, and this revealed a dilliculty
the males and 85% of the females having less t
in obtaining the long-term co-operation of patients
45 sq. ft (4.2 m2) of living accommodation per pers
treated at home in taking their medicine. More
irregularity in self-administration was found among
female than among male patients.
20% of the families of the males and 48% of
females had less than 25 sq ft (2.3 m2) per pers
11. Toxic manifestations attributed to PAS occurred
in 2.6% <)f (he 193 patients. No toxic clfects were
produced by isoniazid.
12.
Thirteen home and six sanatorium
patients
were admitted to hospital in the course of the
12 months for the investigation or treatment of
non-luhcrculous conditions. Thus a small number
of hospital beds proved to be necessary for the home
series, and
would
be needed
in
any large-scale
Two more males (4"„) were homeless.
20. The income of the males in both series \
gieatly icduccd during treatment but a proport
of the home patients had regained some earn
capacity by the end of 12 months, when 55'.’,,
the 47 males at home were earning.
21. A modest amount of linancial assistance \
given to the families of patients in both scri
more being required for the families of male th
of female patients, and more being required wi
scheme for home treatment.
the patient was treated at home than when he v
13. - Infection with primary isonia/id-icsistant organ
isms occurred in 3.6% of the patients, primary
treated in sanatorium.
resistance to PAS in 2.6% and primary resistance to
22.
streptomycin in 2.2% of the patients.
the families of the 97 patients in sanatorium, th
14. A detailed analysis of smear-positive but culluie-
occurred in only eight in the 96 home families, a
weie also less sei ions; thus, in i/iis xfittly, sanatoria
negative bactei iological findings has shown that
these may be interpreted as negative bacteriological
results.
15.
Ihcie is evidence that dillcicnt ciiteiia of
interpretation should be used for PAS-scnsitivily tests
on Indian strains of tubercle bacilli from those that
apply to British strains.
Whereas major social problems arose in 20
treatment proved more disruptive to family life.
23. Twelve of (he 97 sanatorium patients we
dischaiged during the 12 months (though fo
were only temporary discharges) whereas only oi
of the 96 home patients discharged himself fro
treatment. It proved easier to keep the co-operatk
of the home patients.
16. At the start of treatment the great majority of
patients had low incomes, by current Indian stand
ards, and came from families with low total incomes.
24. It is concluded that the results of domicilia
chemotherapy, as carried out in this study, approai
sullicicntly closely the results of sanatorium trea
17. I he diet T the home and sanatorium scries
was similar before the start of treatment, but
ment to suggest that it is appropriate to treat tl
majority of patients at home. In formulating th
there were important differences during treatment,
the sanatorium diet being clearly superior. Thus,
conclusion, consideration
in terms of animal protein, 84% of the males and
97% of the females at home had less than 30 g a
namcly, rcst^dict, nursing and supervised medicine
taking on the one hand, and the social disadvai
day, compared with no patient of either sex in
tages. as represented by the disruption to family lit
and the dilliculty of persuading patients to remai
in sanatorium, on the other. It is recognised th?
sanatorium.
18. The
mote
icst;
manifest
advantages
of
has
been given to tl
sanatorium
treatment-
at
the standards of medical caie during this study wcr
12 months, 19% of males and 10% of females were
very favourable, but it is considered that comparabl
sanatorjnm
patients
had
allowed up for four hours a day, whereas at home
results should be obtainable from a domiciliar
80% of the males and 91% of the females had
service which is being operated from a tuberculosi
clinic, provided that certain minimum requirement
returned to part-time or full-time activity, both of
which represent a greater degree of activity than
four hours up for sanatorium patients.
arc met. Among these arc an adequate supply o
antituberculosis drugs, enough staff, including>;
HOME AND SANATORIUM CARE OF TUBERCULOSIS
129
public health
U!X7°" | SS °f PatientS in
‘h- -dtcines,
(including an
hospital bed? foir special cases, an cllicicnt appointb lull? ’4n1|,l, C',"",ni“l‘.,nS °f sPl,tl"”
tubercle
bucilli, and
ment system. a system of surprise Checks on the
patiems.*
' ‘‘
h"H ,Or CS|’ceklHy needy
pu lien is.
acknowledgements
vvD| 5. ^a.ni; Direclor of ,lie Soillh East Asia Region
World Health Organization. Dr E. J. T. MeWecney his
WHOA1" r'buci,teis. Dr M !<■ Sacks, lately lhe
Representative for India and Dr I Hnt™
Ch,er
OHieer.
n untcable Diseases. WHO,
llcl, .a|„ah|c
.
•'I every stage of (he work.
who Area
It would not have been possible to complete the studv
"a "! .T0"'
dC™‘Cd -K <>“ !-
t■ rnl n
’( lbo,alOry’ s,u"^ieal, radiographic, secrearta and admmistrative. The efforts of the public
’'n.H"","?' hCa"h ViSi,°rS Md SO“I workers made
particularly important contribution to keeping the
co-openmon of (he study patients and their ramifies.
REFERENCES
A"1Xz)R,OHI55& R3dhakris'™. S- (1959) Tuberde
Noretnber 1949 under the auspices of the Tuberculosis
Association of India, New Delhi p 271
Frimodl-Mollcr, J. (1955) India,, J. T,~b„e.. 2 4f
Frtmodt-Molkr, J., Jaudian. K. T. Mmhi lh T S n, f
Ban,,.,. R M (.953)
j.
T' S &
Bbnicke. R. (|958) Hull. int. Un. Tuberc, 28 153
Bierman, I, (|957) In: Transactions of the 16th Con
Ja’r.on.t"^
&
^ZyliZ c;^-t
SXX(1953bi
the J etcrans Administration, Washington’ p ,717M^,
Chaudhun, S (1959) Lancet. 1, 144
Coster, J. F. & Manten, A. (1956) Amer. Rev. Tuberc., 74
9 JO
’
Courdurier, J. & Brygoo, E. (1947) Med. iiop., 7, 254
Crofton, J. (1957) blew. med. J., 25, 45
Di‘n"-‘ls. M Ridehalgh, F„ Springett, V. H. & Hall
• M. (1948) Tuberculosis in young adults, London’
Lewis, p. 217
Dixon, W. M„ Stradling, P. & Wootton, I. D P (1957)
Lancet, 2, 871
East African/Bntish Medical Research Council Sulphone
Investigation (1959) Tubercle (Land.) 40 1
Fox, W. (1958) Tubercle (Land.), 39, 269
F°t I9SM tT0? P/ W” Su,hcrland- E & Williams, A. W.
(1956) Tubercle (Land.), 37, 435
Fox, W. & Sutherland, I. (1956) Quart. J. Med 25 221
L
&
Danids’M
Hwh^V4Js&R-,hakrish„a.S.(1959)
& Swilhi"tak- '■
^1..
(Loud.), 37, J51
India, Ministry of Commerce, Office
—; of the Economic
Adviser (1949) deport on an enquiry into the flimiiy
budpets of middle class
enqdoyce.s of the Central
Coreimnent, Simla, p. 2
(i95^
w.'i.t?0 J<’,,l,io"x’ E-(,957J Rev f a^
Clin.
Fox, W. Wiener, A., Mitchison, D. A., Selkon, J. B &
Sutherland, I. (1957) Tubercle (Loud.), 38. 71
Kreis, B., Le Joubiomc, E. & Pariente, D. (1956) Ann.
^rTu{b^rcM°^r'ii V 9491 1,1'
<>/ the Seventh
/"st. Pasteur, 91 932
Tuhcculosis Markers' Conference held in Homl.av,^ McGregor, I. \. 1 Deegan.
r. (1954) Ann. trap. Med.
130
i uhi:r( ul(wis < i h;m< > 11ii-rai’y CLNlRli
Parasit., 48, 220
°02& Dress'er’s' H' (I9M>
Tyrrell W. F. 0956)
2, 82|
"•R ■
a1
78t 735
»•
’■229
’ ‘ <*958) Amer. Rev. Tuberc.,
Selkon, J. B. & Milchison. D. A. (1959) Tubercle (Loud.)
Simpson J. McD. (1956) Tubercle (Loud.), 37 333
Slewan. S. M. (1955) J. ell.,. Pud,.. 8, 237
w"b o,5S,; Tcd’
'•f the I Sth Conference on the rt 956,/n- Tl factions
cuiodr i,M p..br,.ary x;: m
p. 60“""' ''
Vmra''s ^'"mlstrution, Washinpon,'
^I'wOn'.^’ °- L ’ Ta,lor’ R- L-
Fraser R S
A-Parker’M-v-&
w. B. (1955) Amer. Rev. Tuberc., 72 119
msn17,1 S7ie;r or,Sto'b"d. Research Committee
(l >57) Tubercle (Loud.), 38, 375
T'^en W. 11. & Livings, D. Ci. (1955) Amer. Rev. Tuberc..
w (1957) Amer R, u r
K- 5. &Stccnken,
u/
... .
z,w,,• «-•»’. lubcrc., 76 497
Wynn-Williams, N. & Arris M (195X1 v /
/ z
39, 138
’
(l95^ labercle (Loud.),
-j
468
Tubercle, Land., (1959), 40, 468
ABSTRACT
y°y
should, of course, be referred to for points of detail.
5
A Concurrent Comparison of Home and Sanatorium
Treatment of Pulmonary Tuberculosis in South India*
Tuberculosis Chemotherapy Centre, Madras
In India, as in most under-developed countries, the tuberculosis problem is appravated
by an acute shortage of sanatorium beds. The number of active cases of tuberculosis in the
country has been estimated at 2$ million, but only 23,000 tuberculosis beds are available,
n hese circumstances great importance attaches to the possibility of applying mass domiciliary
chemotherapy as a substitute for sanatorium treatment in cases of pulmonary tuberculosis.
1 he findings of the present study, based on a comparison of the two types of treatment over
a period of twelve months, show that despite the manifest advantages of sanatorium care diet’ nurSing
supervised medicine-taking - the merits of domiciliary
chemotherapy are comparable to those of sanatorium treatment, and that it would therefore
be appropriate to treat the majority of patients at home, provided an adequate service were
established.’
1
I. Introduction
The Tuberculosis Chemotherapy Centre, Madras, was set up in 1956 ‘under the
joint auspices of the Indian Council of Medical Research (ICMR), the Madras
State Government, the World Health Organization (WHO) and the Medical
Research Council of Great Britain (MRC). The senior scientific staff of the Centre,
who are responsible for the work reported here, are: Dr Wallace Fox (WHO)
SCT°cr ^dical Officer; Drs R. H. Andrews (WHO), C. V. Ramakrishnan (ICMR),’
and b. Velu (Madras Government), Medical Officers; Dr S. Devadatta (ICMR)
Assistant Medical Officer; Drs A. L. Bhatia (ICMR), D. A. Mitchison (WHO)
and J. B Selkon (WHO), Bacteriologists; Dr P. R. J. Gangadharam (ICMR)t
Miss E’ Ho,st (WHO)’ Laboratory Technician; Mr T. V.
bubbaiah (ICMR), Laboratory Research Assistant; Mr S. Radhakrishna (Madras
Government), Statistician.
inl/n research of the Centre is guided by a Project Committee consisting of three
ICMR representatives (Drs P. V. Benjamin, Convenor, J. Frimodt-Moller and
K. S. Sanjivi), the Director of the ICMR (Dr C. G. Pandit), the Director of
Medical Services, Madras State (first Lt-Col Sangham Lal and then Dr V. R.
Ihayumanaswamy), a WHO representative (appointed for each meeting), an
MKG representative (appointed for each meeting) and the Senior Medical Officer
w n c ■i?trC (Dr Wal,acc Fox)- The joint secretaries are Mrs K. Daniels and
Mr B. S. Verma.
7 he MRC, through its 7 uberculosis Research Unit, is responsible for the scientific
direction of the research, in accordance with plans prepared by the Project
Committee. Dr Wallace Fox of the Tuberculosis Research Unit has been seconded
’ ?u^rT/rOmn“^rC/^nJ ) 40 (1959) 468’476' With
^“ion of ^e Managing Editor
Tubercle & Lung Disease. Churchill Livmgstone Medical Journals. Edinburg. United Kinfdot
Medical Journals. Edinburg. United Kingdom
-X
HOME AND SANATORIUM TREATMENT
469
to WHO to serve as the Senior Medical Officer and the Director of Research at the
Centre, and the laboratory was established by Dr D. A. Mitchison of the MRC
Group for Research on Drug Sensitivity in Tulrcrculosis. Close contact is maintained
between the Centre in Madras, the MRC Tuberculosis Research Unit (Dr P.
D Arcy Hart) and the Group for Research on Drug Sensitivity in Tuberculosis
(Drs D. A. Mitchison,
B. Selkon and J. G. Wallace) in London. Dr lan
Sutherland of the MRC Statistical Research Unit has advised on statistical aspects.
In India, Drs Ida B. Scudder and J. Tri mod t- Moller acted as independent
radiological assessors, and Drs C. Gopalan and V. N. Patwardhan of the ICMR
Nutritional Research Unit have advised on the dietary study referred to in this
report.’
‘1 he study was designed to yield information on the following aspects of the
treatment of pulmonary tuberculosis among patients living in an adverse urban
environment in India:
(1) I he relative merits of home and sanatorium treatment with standard
chemotherapy.
(2) 1 he extent to which the infectivity of a series of patients treated at home can
be reduced by standard chemotherapy.
(3)
prevalence of tuberculosis in family contacts at the time of diagnosis of
the index case and the subsequent incidence of tuberculosis among them, with
particular reference to the drug sensitivity of the strains.
(4) The identity and virulence of the causative organisms and their comparison
with strains of tubercle bacilli from England.
(5) Some of the practical procedures involved in the mass application of
chemotherapy - for example, methods of sputum collection, of checking the selfadministration of medicines and of general supervision of patients.
(6) Diet and its relation to the response of chemotherapy.
(7) The causes and management of treatment failures.
The present report is concerned principally with the first two of these points.
The others will be considered fully in later reports.’
II. General Plan and Conduct of the Study
Patients with pulmonary tuberculosis were selected from those attending local chest
clinics in Madras City and living in a defined area, the final limits of which embraced
• population of about 750,000. Most of the patients came from the poorest section
of the community. They were selected for the study if they fulfilled all the following
conditions:
(1) The patient had either had no previous antituberculosis chemotherapy,
or antituberculosis chemotherapy had been administered for not more than
two weeks.
(2) The patient was aged 12 years or more (sanatorium beds were not available
for younger children).
(3) The sputum was positive for tubercle bacilli either on direct smear
examinauon or on culture.
(4) The patient was living in Madras City in the defined area of intake (and
‘h“’acccs?lble for home visiting) and was likely to remain so for several yeap.
(5) The patient was prepared to:
'
(a) accept treatment either at home or in sanatorium for at least a year.
(b) accept treatment whether with pills or inj’ections.
(c) permit home visiting.
*nel‘8*b'c any
the following applied at the start of treatment:
(1) The patient was too ill for home treatment (e.g. was nearly moribund,
had a spontaneous pneumothorax or had had a severe haemoptysis).
470
T UJIBR CLP.
(2) The patient had a pleural effusion obscuring more than one-third of a
lune field, as seen on a postero-anterior chest radiograph.
(3) The patient had a non-respiratory form of tuberculosis which it was
considered would complicate treatment.
1OWII to
lu iiavv
.
(4) The patient was known
have leprosy.
as
known to- have
(5) The patient was k
----- a serious concomitant disease such
dialxttcs.
(6) The patient was known to be pregnant.
,
A sample of 10 pre-treatment radiographs drawn at random from th' grouP ®
patients treated at home (the group of especial interest) is illustrated in an Appendix.
at random to two regimens of trca|tn’fnut;^thi> were to
at home,. the other
receive the same chemotherapy; one group was to be
1.^treated
-----------------in sanatorium.
CACa°cheJ each containing 25 mg. isoniazid and 1 25 g- ^xliuJn
k^Ht
daily dose varied with the patient’s weight; for those less than 80 lb. (36 3 kg. it
wasy|5o mg. isoniazid and 7-5 mg. sodium PAS (3 .cachets morning and evemg)
and for patients of too lb. (45-4 kg.) or more 200 mg. isoniazid and to g sodium FAb
(4 cachets morning and evening). The dose of isoniazid was greater than 4 mg./kg.
body weight in all but a very few patients.
,/0‘7n KTudy home treatment meant the ^eatment of patients in
with clinic supervision of their progress. Chemotherapy was started immejatdy
after allocatiorTof the treatment and the majority of the ho™
endJn
the Centre weekly throughout the twelve months for supplies of mcdici e
addition a visit was usually paid to the home each week thirii.R
a he ilth visitor and less regularly by a doctor or a public health nurse. Less frequent
holne vi.™ “1=
iXe. U<b.. 1. «»s
Co. fewer .tan
■ taw.
to be made each month, because one was made to deliver a sputum
and one-an unexpected visit - to collect a specimen of urine^to be ‘«tcd f"r ,h£
presence of PAS, as a check that the patient was taking the medicine. Patients
initially too ill to attend weekly rested at home for the first month and were the
brought up by ambulance for re-examination and assessment. As soon asi hey had
imornved sufficiently they were changed to the ordinary routine of visit, to the
Centre and the home.’ iL y were encouraged lo stop work and rest. 1 he ma.ion y
were u , and about much of the time and quite often not at home when visited.
When medically fit to return to work they were encouraged to do so.
.i.i, B™p were rd.„i..ed
Government Tuberculosis Sanalonum 1 ambaram. I hey restecHr.bed'
*
they were allowed to go home for one day, if fit, once a month.
III. Bacteriological Procedures
Scutum was examined before treatment and at monthly intervals throughout
by
m or^
I
HOME AND SANATORIUM TREATMENT
47,
472
bv
7?CrT;Opr With
according to the density of bacilli, and
by culture on LOwenstein-Jensen medium, the results also lieing graded
Sensitivity tests to streptomycin, PAS and isoniazid were carried out on two
teX rwrT«?uDUfrom theV"
m°n‘h throu8hou‘ treatment. The
1
■
sanatorium. The corresponding proportions for the females were 45 per cent and
26 per cent.
Thus, the two groups were not equivalent in some important factors before
treatment l>egan, the home groups in both sexes having more severe disease, and
the difference being greater among the females than the males.
V. Comparison of Home and Sanatorium Treatment in Males
Draths: There were two deaths among the 49 in the home series (1 from tuberculosis
in the eighth week; 1 from an accident at work) and 1 (from tuberculosis) in the
50 of the sanatorium series.
Change of chemotherapy. - One patient at home deteriorated after initial improvement
and treatment was changed after nine months to streptomycin and pyrazinamide.
There were minor modifications of dosage or short interruptions of chemotherapy
in a few patients in both series, insufficient to justify removing them from the main
analysis.
Clinical changes. - At the end of twelve months the sanatorium males had gained
more weight (1 7-8 lb. compared to io-6 lb.) and had lower ESRs, both differences
attaining statistical significance.
Radiographic changes. - The differences between the series were small, though those
treated in sanatorium had slightly more with considerable radiographic improvement
over the twelve months period (50 per cent sanatorium, 39 per cent home). Among
the sanatorium group a higher proportion were judged to have no x-ray evidence
of cavities (on tomography) at twelve months (50 per cent sanatorium, 38 per cent
home), having had cavities initially. The home series did, however, have more
severe disease before treatment and when allowance was made for this the progress
of the two groups of patients showed an even closer similarity.
Haiterinbigical changes. -There was a striking decline in the bacterial content of the
sputum in both series, with little difference Irctwecii them. With single specimens
taken at monthly intervals the proportions still positive on culture at three, six,
nine and twelve months in the two groups were: home - 36 per cent, 13 per cent,
13 per cent, 9 per cent; sanatorium - 26 per cent, 4 per cent, 6 per cent, 10 per cent.
The disease was considered to be ‘baclcriologically quiescent’ at twelve months if
alt the cultures for at least the last three monthly examinations had been negative.
The total cultures set up for each patient each month from the third month onwards
could be 4 - two sputum specimens and two laryngeal swalis. Thus, the definition
of‘bacteriological quiescence’ was a very stringent one. ‘Bacteriological quiescence’
was reached by 38 (78 per cent) of the 49 home patients and 41 (82 per cent) of
the sanatorium patients. There was a tendency for sputum conversion to occur
earlier in the sanatorium group: 68 per cent of those who attained ‘bacteriological
quiescence’ had negative cultures by three months compared with 50 per cent of the
home patients.
Isoniazid sensitivity. - At six months 5 of the 7 positive cultures in the home group
were resistant, compared with all of the 4 positive cultures in the sanatorium group.
At twelve months the proportions of the total patients with resistant cultures were
94>cr cent of the home scries and 4 per cent of the sanatorium. Four patients (2 in
each group) still had sensitive cultures.
- th'
Definitions of Resistance
Isoniazid:
Growth on 11 ug
/ml. or a higher concentration,
Hg./ml.
or growth on
0 2 pg./ml. provided that a repeat test on the same strain yielded
growth on 0 2 pg./ml. or a higher concentration.
PAS:
Pre-treatment tests: a resistance ratio of more than 8, or if there
we£ ol2JtTUnCC ral,<T’f 8 a"d 4 Ol’ mOrc- or ir,hree ra‘i“ of 4
.h
d f,°m am0,'g ‘hc tCSts 011 thc two Pre->reatment cultures
‘he two repeat tests on these cultures. Post-treatment tests:
either a resistance ratio of 8 or more, or a resistance ratio of 4,
followed by a ratio of 4 or more in a repeat test
Streptomycin: A resistance ratio of 8 or more, or a ratio of 4 followed by a ratio
of 4 or more in a repeat test.
}
IV. The Patients Allocated to Treatment
™^C,,h.er 193 Pa.tienu, werc allocated to the two groups, 96 to home treatment
and 97 to sanatorium, between September 1956 and Septemlier io<;i For a •
fXT-30 (VOniC- 16 ?ai,alor'un,) COuld
S for the5maH analyst
(9 had isoniazid-resistant cultures before treatment ami 6 PAS-resistant■ 4 althoLh
having sensitive cultures, were found on further enquiry to have had morc han
nflu*± ,Chhemothcrapy i" ’he Past; 2 died from nomtuberculous dis^« tha"
influenced the course of the tuberculosis; 2 had prolonged or intrac abk PAS
ti“‘«?n;8re.reprerna,7c|yidis‘harKed from treatment (. home, 7 Stori urn)
and 3 patients liemg treated at home were udmiited to Inwniml or /„ , •
r ’
SiX Weeks)-
I‘hC. -h’ a‘‘a>y"s
TUBERCLE
rhere we^/g
Pat‘en’s (82 home, 81 sanatorium), who had organisms sensitive to isoniazid and
treatment Jgime
<,r . ........
' ,,,",1’"l<-l>y «nd followed the alloLled
Pre-treatment Comparison Between the Croups
In spite of the random allocation procedure being rigorously observed there
S.KX.
in ,h' Pre•,rea,m“,
Rpdiopaphic - All radiographic assessments of initial state and of change were made
VL Comparison of Home and Sanatorium Treatment in Females
The pre-treatment differences were greater in the females than in the males. Differences in
response during the treatment period should therefore be interpreted with great caution [see
section VII).
Deaths. - One patient in sanatorium died of tuberculosis after five days’ treatment.
MM
■
..
■
■
TUBERCLE
473
HOME AND SANATORIUM TREATMENT
Clmg, a/dWdWapy.-Tn . .pa.W
S
474
« I
r«'““ "ilb
“re
“JXt” a!’™, end of tiv^ mon.h, .be -ana.oHum group bad gWed
process
in response arising from pre-treatment differences.
the home series and 61 per cent of the sanatorium.
Bacteriological change. - The proportions wit P^S,JV'[<JJ,r
sneciniens
, sanatorium
at—mon,hs
by 67 per cent at home and 94 per cent in sanatorium.
before the Start of
.r
vm. rr^o-de
Lunfavourable
h:,T!.uiXprognostic
gg^\signs.
aK
IX. Further Bacteriological Findiuga
Snuar-positiM Culturt-Negalivt Results
Thr<Keum«e of
Uye results before the start of
.
In the middle
treatment was rare. Such res "
. decreased. The result was an isolated
^t.onTSmio”,y ofp^en^mdU
^Xblem
vn.
uh— or J-ffiSSr
S'ri“
S'S aVSe: lay^h.. the badlli m .bme .poeimem were mm-v»ble.
Isoniazid Resistance
isoniazid-resistant cultures during
resistant cultures; ano‘hc | 8 ,i(.dnts (q.8 per cent of the whole group) may have
of"danger’^he puSic health during the study and perhaps
improvement at twelve months were 40 4 per cen
•
, 1(IC| yv|1(;n Ixilh
9 With the males the pattern was very similar to that of the whole group, namely
a small residual advantage in radiographic < liangc to the males treated in saiialm nun,
who had fared a little lielter than those at home. With lemales, on the other hand
standardization for the same two pre-treatment differences simultaneously rcvcised
the position in terms of considerable radiographic improvement at six months, the
proportions changing from 30 3 per cent for those at home and 43 3 per cent <>r
those in sanatorium to 32-I per cent and 30 4 l>cr cent respectively. At twelve
months the corresponding standardized figures were 44 3 per cent and 39 9 pei cent.
With cavity closure the contrast between the series almost disappeared, the
standardized proportions at twelve months being 49 per cent at home and 51 per
cent in sanatorium. In summary, there was little to choose between the two groups
of females after allowance had been made for pre-treatment radiographic differences.
Similar analyses concerning the bacteriological response showed that taking into
account the pre-treatment radiographic condition almost removed the barter il
logical disadvantage to the males treated at home; but the disadvantage to 1 c
females at home remained. Thus, the proportions of males W'U’
quiescent’ disease at twelve months changed very little with standardization, fi
89 4 per cent home and 99 8 per cent sanatorium to 91 4 and 86 6 P" ^1
respectively. But the difference with the females remained large and almos
unaltered, the standardized proportion being 75 5 Pcr cent home and 100 per cent
sanatorium.
■"SXto who ..dined ^.erio'o^^m^e
I26 (97 percent) had y.elded only isomand^mt.ve r«
4
d
resulu. Ten had disease of'status a"derhaJ had resistant cultures.
positive with isonWd.mm.tive
cultures throughout the whole twelve months.
PAS Sensitivity
,
At six months 3 of the 15 strains
d
q of 17. Cultures remained positive, a
longer period after the emergence o is
of PAS resistance. This suggests th
^£^7X^7^
re5isftnt to PAS and at twelve months
silivc t0 the
the companion
companion drug,
drug, for a
rr.i,.ance than after the emergence
j.
of jsoniazid resistance is associated
positivity than a finding
finding of
ofJAS
PAS
by resistance
’
tife imnim^tivi.y msulti were 1Mhl,
consistent, whereas the PAS res'‘lt’
^uerpVctcd in this study, were considered
•PAS sensitivity tests, as,«rned tfst<d being9inconsistent and less indicative of a
ofUumce.. .ha oW d«g emmgmg.
x. Toxicity and Other Complications
account of them.
I
BI
I
i
HOME AND SANATORIUM TREATMENT
475
At most only 5 (a-6 per cent) had hypersensitivity or other toxic reactions to PAS.
There was no suspicion of isoniazid toxicity in any patient.
It was necessary during the twelve months to admit to hospital 19 of the patients
being treated at home; 6 had complications of the pulmonary tulierculosis or of
treatment, 13 had non-tuberculous conditions.
XL Self-administration of the Medicine
Two methods were used to check regularity of self-administration - urine tesling
<-r k S ar|d counts of the patient’s stock of cachets. Among the men, 40 per cent
of those at home gave positive urine tests in each of the twelve months and 96 per
cent of those in hospital.-Twenty-six per cent of the male patients at home gave one
or more negative tests in at least three of the months. Among the women only
27 per cent of those at home gave positive results throughout and only 63 per cent of
those in hospital. Thirty-three per cent of the female patients at home gavc one or
more negative results in at least three of the months.
Cachet counts at surprise visits to the patient’s home showed inaccuracies in the
number of cachets that should have remained from the prescribed stock in 6-6 per
cent of the checks on men and 9 per cent on women. In 5 patients the inaccuracy
was large enough to suggest that the patient had completely stopped taking the
There was no clear-cut evidence that those patients who had negative urine tests
during treatment or inaccurate cachet counts fared less well than the remainder.
!
1
si
XII. Various Social Factors
The diet of the patients was investigated to discover differences between those
treated at home and those at sanatorium. Before the start of treatment the diets of
both groups were similar. During treatment, however, there were major differences,
lhe daily intake was less than 2,000 calories in 42 per cent of home male patients,
compared with only 4 per cent of those in sanatorium. For females the corresponding
proportions were 61 per cent and 3 per cent. Forty-four per cent of the males and
bi per cent of the females at home were receiving less than 50 g. of protein a day,
compared with none of those in sanatorium. The animal protein content of the diet
was less than 30 g. in 84 per cent of the males and 97 per cent of the females at home,
compared with none in sanatorium. The home series appear, therefore, to have
been at a very considerable dietetic disadvantage.
The majority of the home patients were living in overcrowded conditions, the
iamiha of 68 per cent of the males and 85 per cent of the females having less than
45 »q- leet (4 a sq. metres) of living space per person; 20 per cent of the families of
the males and 48 per cent of the females had less than 25 sq. ft. (2-3 sq. metres),
lhe income of the males m both series, already low by current Indian standards,
pcally reduced during treatment but a proportion of the home patients had
regained some earning capacity by the end of the twelve months, when 55 per cent
of the 47 males at home were earning.
A small amount of financial assistance was given to families of patients in both
senes, more being required for the families of male patienu and more when the
patient was treated at home than in sanatorium.
Great attention was paid by the clinical staff of the Centre to the welfare of the
patients and their families; and a great deal of sociological information was obtained
and recorded in the social workers’ records. There were major sociological problems
in 8 percent of the families in the home series: in the sanatorium series the proportion
was 21 per cent. In the home series 5 families split and there were 3 serious family
quarrels. In the sanatorium series there was temporary or continued desertion or
lanuly split m 20 cases and serious home difficulties in 5. There is little doubt that
476
TUBERCLE
^iXSffisSTtagL^ PatientS
a sanatorium for twelvc
“™ed
X1IL Subsidiary Group, of Patients Not Included in the Main Analysis
Patients with Resistant Organisms Before Treatment
.
rh.t9 W’th !"itial,y «onia»<i resistant cultures it is considered that 7 (3-6 per
trip.1<; drug
following an early complication.
thouCht^1??
,n,tl?Ily PAS:Tistant cu,tur« 5 (2 6 per cent of the 192) are
thought to have been infected with resistant organisms. The one who had had
wXTd±r0,hHraPy-di-ZCl1- ThreC °f thc 5 *ith PHmary rcsistance also fared
^n'awd-resntance and 1 eventually did well after receiving
streptomycin and isoniazid.
6
Pre-treatment resistance to streptomycin was found in 5 cultures. It is likely that
<a-a P" ccnt of ’®3 patients) there had been infection with a
rcsiscani strain.
Premature Discharge from Treatment
Much difficulty was encountered in persuading many of thc patients to remain
m sanatorium for the full twelve months. In spite of all the efforts of the staff q
patients absconded and 3 had to be discharged for disciplinary reasons. Five of
hose who absconded returned after a short interval and have been included in
the main analysis. All of the remaining 7 patients not included were examined at
the end of the twelfth month: 3 were still infectious, 2 with resisUnt organisms.
• °a- ’
absc?,ndcd1 from ‘raiment in the home series. He had developed
jaundice which he attributed to the treatment.
H
Contrary to all expectations, it was, therefore, more difficult to ensure that
patients continued treatment in sanatorium than to persuade patients to remain,
under treatment at home.
Conclusion
It is concluded that the results of domiciliary chemotherapy, as carried out in this
study, approach sufficiently closely the results of sanatorium treatment to suggest
that it is appropriate to treat the majority of patients at home. In formulating this
conclusion, cons.deration has been given to the manifest advantages of sanatorium
treatment namely, rest, diet, nursing and supervised medicine-taking - on the one
hand and the social disadvantages, as represented by the disruption to family life
and the difficulty of persuading patients to remain in sanatorium, on the other.
It is recognized that the standards of medical care during this study were ven'
favourab e, but it is considered that comparable results should be obtainable from
a domiciliary service which is being operated from a tuberculosis clinic, provided
that certain minimum requirements are met. Among these are an adequate supply
of antituberculosis drugs, enough staff, including a public health nurse and a social
worker, transport (including an ambulance), a small number of hospital beds for
special cases, an efficient appointment system, a system of surprise checks on the
cb-operation of the patients in taking their medicines, reliable smear examinations
Of sputum for tubercle bacilli and a welfare fund for especially needy patients.’
- Media
RF-TB-1.2.pdf
Not viewed